RESUMO
BACKGROUND: N-acetyltransferase 10 (NAT10) plays a crucial role in the occurrence and development of various tumors. However, the current regulatory mechanism of NAT10 in tumors is limited to its presence in tumor cells. Here, we aimed to reveal the role of NAT10 in intrahepatic cholangiocarcinoma (ICC) and investigate its effect on macrophage polarization in the tumor microenvironment (TME). METHODS: The correlation between NAT10 and ICC clinicopathology was analyzed using tissue microarray (TMA), while the effect of NAT10 on ICC proliferation was verified in vitro and in vivo. Additionally, the downstream target of NAT10, C-C motif chemokine ligand 2 (CCL2), was identified by Oxford Nanopore Technologies full-length transcriptome sequencing, RNA immunoprecipitation-quantitative polymerase chain reaction, and coimmunoprecipitation experiments. It was confirmed by co-culture that ICC cells could polarize macrophages towards M2 type through the influence of NAT10 on CCL2 protein expression level. Through RNA-sequencing, molecular docking, and surface plasmon resonance (SPR) assays, it was confirmed that berberine (BBR) can specifically bind CCL2 to inhibit ICC development. RESULTS: High expression level of NAT10 was associated with poor clinicopathological manifestations of ICC. In vitro, the knockdown of NAT10 inhibited the proliferative activity of ICC cells and tumor growth in vivo, while its overexpression promoted ICC proliferation. Mechanically, by binding to CCL2 messenger RNA, NAT10 increased CCL2 protein expression level in ICC and their extracellular matrix, thereby promoting the proliferation of ICC cells and M2-type polarization of macrophages. BBR can target CCL2, inhibit ICC proliferation, and reduce M2-type polarization of macrophages. CONCLUSIONS: NAT10 promotes ICC proliferation and M2-type polarization of macrophages by up-regulating CCL2, whereas BBR inhibits ICC proliferation and M2-type polarization of macrophages by inhibiting CCL2.
Assuntos
Proliferação de Células , Quimiocina CCL2 , Colangiocarcinoma , Macrófagos , Quimiocina CCL2/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Macrófagos/metabolismo , Humanos , Animais , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Masculino , Microambiente Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Polaridade Celular/efeitos dos fármacos , Camundongos Nus , Camundongos , Pessoa de Meia-Idade , Ligação ProteicaRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant, rapidly progressing tumor of the bile duct. Owing to its chemoresistance, it always has an extremely poor prognosis. Therefore, detailed elucidation of the mechanisms of chemoresistance and identification of therapeutic targets are still needed. METHODS: We analyzed the expression of MBD2 (Methyl-CpG-binding domain 2) in CCA and normal bile duct tissues using the public database and immunohistochemistry (IHC). The roles of MBD2 in CCA cell proliferation, migration, and chemoresistance ability were validated through CCK-8, plate cloning assay, wound healing assays and xenograft mouse model. In addition, we constructed a primary CCA mouse model to further confirm the effect of MBD2. RNA-seq and co-IP-MS were used to identify the mechanisms by how MBD2 leads to chemoresistance. RESULTS: MBD2 was upregulated in CCA. It promoted the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 directly interacted with WDR5, bound to the promoter of ABCB1, promoted the trimethylation of H3K4 in this region through KMT2A, and activated the expression of ABCB1. Knocking down WDR5 or KMT2A blocked the transcriptional activation of ABCB1 by MBD2. The molecular inhibitor MM-102 targeted the interaction of WDR5 with KMT2A. MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin. CONCLUSION: MBD2 promotes the progression and chemoresistance of CCA through interactions with WDR5. MM-102 can effectively block this process and increase the sensitivity of CCA to cisplatin.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Proteínas de Ligação a DNA , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Humanos , Animais , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Proliferação de Células , Linhagem Celular Tumoral , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Ensaios Antitumorais Modelo de Xenoenxerto , Movimento Celular , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genéticaRESUMO
Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients.
Assuntos
Carcinoma Hepatocelular , Colangiocarcinoma , Glicerofosfolipídeos , Metabolismo dos Lipídeos , Neoplasias Hepáticas , Humanos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Glicerofosfolipídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Metabolômica/métodos , Progressão da Doença , Fosfatidilcolinas/metabolismo , Lisofosfatidilcolinas/metabolismo , Idoso , Fosfolipases A2/metabolismo , Reprogramação MetabólicaRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified. METHODS: We confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclearâcytoplasmic separation and immunofluorescence experiments. The downstream PLA2G2A gene, regulated by the STUB1-UHRF1/DNMT1 axis, was identified via RNA-seq. The negative regulatory mechanism of PLA2G2A was explored via bisulfite sequencing PCR (BSP) experiments to assess changes in promoter methylation. The roles of PLA2G2A and STUB1 in the proliferation, invasion, and migration of CCA cells were assessed using the CCK-8 assay, colony formation assay, Transwell assay, wound healing assay and xenograft mouse model. We evaluated the effects of STUB1/UHRF1 on cholangiocarcinoma by utilizing a primary CCA mouse model. RESULTS: This study revealed that STUB1 interacts with UHRF1, resulting in an increase in the K63-linked ubiquitination of UHRF1. Consequently, this facilitates the nuclear translocation of UHRF1 and enhances its binding affinity with DNMT1. The STUB1-UHRF1/DNMT1 axis led to increased DNA methylation of the PLA2G2A promoter, subsequently repressing its expression. Increased STUB1 expression in CCA was inversely correlated with tumor progression and overall survival. Conversely, PLA2G2A functions as a tumor suppressor in CCA by inhibiting cell proliferation, invasion and migration. CONCLUSIONS: These findings suggest that the STUB1-mediated ubiquitination of UHRF1 plays a pivotal role in tumor progression by epigenetically silencing PLA2G2A, underscoring the potential of STUB1 as both a prognostic biomarker and therapeutic target for CCA.
Assuntos
Neoplasias dos Ductos Biliares , Proteínas Estimuladoras de Ligação a CCAAT , Colangiocarcinoma , Metilação de DNA , Progressão da Doença , Ubiquitina-Proteína Ligases , Ubiquitinação , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Camundongos , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Masculino , Proliferação de Células , Feminino , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genéticaRESUMO
BACKGROUND: Epigenetic modifications, such as DNA methylation and histone modifications, are pivotal in regulating gene expression pathways related to inflammation and cancer. While there is substantial research on epigenetic markers in cholangiocarcinoma (CCA), Opisthorchis viverrini-induced cholangiocarcinoma (Ov-CCA) is overlooked as a neglected tropical disease (NTD) with limited representation in the literature. Considering the distinct etiological agent, pathogenic mechanisms, and pathological manifestations, epigenetic research plays a pivotal role in uncovering markers and potential targets related to the cancer-promoting and morbidity-inducing liver fluke parasite prevalent in the Great Mekong Subregion (GMS). Emerging studies highlight a predominant hypermethylation phenotype in Opisthorchis viverrini (O. viverrini) tumor tissues, underscoring the significance of abnormal DNA methylation and histone modifications in genes and their promoters as reliable targets for Ov-CCA. PRINCIPAL FINDINGS: Relevant published literature was identified by searching major electronic databases using targeted search queries. This process retrieved a total of 81 peer-reviewed research articles deemed eligible for inclusion, as they partially or fully met the pre-defined selection criteria. These eligible articles underwent a qualitative synthesis and were included in the scoping review. Within these, 11 studies specifically explored Ov-CCA tissues to investigate potential epigenetic biomarkers and therapeutic targets. This subset of 11 articles provided a foundation for exploring the applications of epigenetics-based therapies and biomarkers for Ov-CCA. These articles delved into various epigenetic modifications, including DNA methylation and histone modifications, and examined genes with aberrant epigenetic changes linked to deregulated signalling pathways in Ov-CCA progression. CONCLUSIONS: This review identified epigenetic changes and Wnt/ß-catenin pathway deregulation as key drivers in Ov-CCA pathogenesis. Promoter hypermethylation of specific genes suggests potential diagnostic biomarkers and dysregulation of Wnt/ß-catenin-modulating genes contributes to pathway activation in Ov-CCA progression. Reversible epigenetic changes offer opportunities for dynamic disease monitoring and targeted interventions. Therefore, this study underscores the importance of these epigenetic modifications in Ov-CCA development, suggesting novel therapeutic targets within disrupted signalling networks. However, additional validation is crucial for translating these novel insights into clinically applicable strategies, enhancing personalised Ov-CCA management approaches.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Metilação de DNA , Epigênese Genética , Opistorquíase , Opisthorchis , Via de Sinalização Wnt , Colangiocarcinoma/parasitologia , Colangiocarcinoma/genética , Opisthorchis/fisiologia , Animais , Humanos , Opistorquíase/parasitologia , Opistorquíase/complicações , Neoplasias dos Ductos Biliares/parasitologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Cholangiocarcinoma (CCA) is an extremely aggressive malignancy arising from the epithelial cells lining the bile ducts. It presents a substantial global health issue, with the highest incidence rates, ranging from 40100 cases/100,000 individuals, found in Southeast Asia, where liver fluke infection is endemic. In Europe and America, incidence rates range from 0.42 cases/100,000 individuals. Globally, mortality rates range from 0.22 deaths/100,000 personyears and are increasing in most countries. Chemotherapy is the primary treatment for advanced CCA due to limited options from latestage diagnosis, but its efficacy is hindered by drugresistant phenotypes. In a previous study, proteomics analysis of drugresistant CCA cell lines (KKU213AFR and KKU213AGR) and the parental KKU213A line identified cullin 3 (Cul3) as markedly overexpressed in drugresistant cells. Cul3, a scaffold protein within CUL3RING ubiquitin ligase complexes, is crucial for ubiquitination and proteasome degradation, yet its role in drugresistant CCA remains to be elucidated. The present study aimed to elucidate the role of Cul3 in drugresistant CCA cell lines. Reverse transcriptionquantitative PCR and western blot analyses confirmed significantly elevated Cul3 mRNA and protein levels in drugresistant cell lines compared with the parental control. Short interfering RNAmediated Cul3 knockdown sensitized cells to 5fluorouracil and gemcitabine and inhibited cell proliferation, colony formation, migration and invasion. In addition, Cul3 knockdown induced G0/G1 cell cycle arrest and suppressed key cell cycle regulatory proteins, cyclin D, cyclindependent kinase (CDK)4 and CDK6. Bioinformatics analysis of CCA patient samples using The Cancer Genome Atlas data revealed Cul3 upregulation in CCA tissues compared with normal bile duct tissues. STRING analysis of upregulated proteins in drugresistant CCA cell lines identified a highly interactive Cul3 network, including COMM Domain Containing 3, Ariadne RBR E3 ubiquitin protein ligase 1, Egl nine homolog 1, Proteasome 26S Subunit NonATPase 13, DExHbox helicase 9 and small nuclear ribonucleoprotein polypeptide G, which showed a positive correlation with Cul3 in CCA tissues. Knocking down Cul3 significantly suppressed the mRNA expression of these genes, suggesting that Cul3 may act as an upstream regulator of them. Gene Ontology analysis revealed that the majority of these genes were categorized under binding function, metabolic process, cellular anatomical entity, proteincontaining complex and proteinmodifying enzyme. Taken together, these findings highlighted the biological and clinical significance of Cul3 in drug resistance and progression of CCA.
Assuntos
Neoplasias dos Ductos Biliares , Proliferação de Células , Colangiocarcinoma , Proteínas Culina , Resistencia a Medicamentos Antineoplásicos , Humanos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Proteínas Culina/metabolismo , Proteínas Culina/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Fenótipo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gencitabina , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. METHODS: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. RESULTS: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. CONCLUSIONS: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Fatores de Transcrição de Choque Térmico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/tratamento farmacológico , Humanos , Animais , Camundongos , Prognóstico , Fatores de Transcrição de Choque Térmico/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proliferação de CélulasRESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features. METHODS: Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells. RESULTS: The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis. CONCLUSIONS: RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Células-Tronco Neoplásicas , Ribonucleosídeo Difosfato Redutase , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Camundongos , Animais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleosídeo Difosfato Redutase/genética , Linhagem Celular Tumoral , Feminino , Masculino , Biomarcadores Tumorais/metabolismoRESUMO
Developing accurate in vitro models that replicate the in vivo tumor environment is essential for advancing cancer research and therapeutic development. Traditional 2D cell cultures often fail to capture the complex structural and functional heterogeneity of tumors, limiting the translational relevance of findings. In contrast, 3D culture systems, such as spheroids, provide a more physiologically relevant context by replicating key aspects of the tumor microenvironment. This study aimed to compare the metabolism of three intrahepatic cholangiocarcinoma cell lines in 2D and 3D cultures to identify metabolic shifts associated with spheroid formation. Cells were cultured in 2D on adhesion plates and in 3D using ultra-low attachment plates. Metabolic exchange rates were measured using NMR, and intracellular metabolites were analyzed using LC-MS. Significant metabolic differences were observed between 2D and 3D cultures, with notable changes in central carbon and glutathione metabolism in 3D spheroids. The results suggest that 3D cultures, which more closely mimic the in vivo environment, may offer a more accurate platform for cancer research and drug testing.
Assuntos
Colangiocarcinoma , Esferoides Celulares , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Microambiente Tumoral , Técnicas de Cultura de Células , Modelos Biológicos , Reprogramação MetabólicaRESUMO
We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3ß/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment.
Assuntos
Acetil-CoA Carboxilase , Neoplasias dos Ductos Biliares , Movimento Celular , Proliferação de Células , Colangiocarcinoma , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Acetilação , Humanos , Animais , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Camundongos , Acetil-CoA Carboxilase/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.
Assuntos
Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Colangiocarcinoma , Células Neoplásicas Circulantes , Humanos , Colangiocarcinoma/sangue , Colangiocarcinoma/patologia , Biomarcadores Tumorais/sangue , Masculino , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/metabolismo , Feminino , Pessoa de Meia-Idade , Prognóstico , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Idoso , Antígenos Comuns de Leucócito/metabolismo , Queratinas/metabolismoRESUMO
Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.
Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Isocitrato Desidrogenase , Mutação , Piperidinas , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/antagonistas & inibidores , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Piperidinas/farmacologia , Antineoplásicos/farmacologia , Quinolizidinas/farmacologia , Proliferação de Células/efeitos dos fármacosRESUMO
Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Triptofano Hidroxilase , Ensaios Antitumorais Modelo de Xenoenxerto , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Animais , Triptofano Hidroxilase/metabolismo , Triptofano Hidroxilase/antagonistas & inibidores , Humanos , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Camundongos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Gencitabina , Cisplatino/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sinergismo Farmacológico , Modelos Animais de Doenças , Serotonina/metabolismo , FemininoRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium that is commonly found in the Thai population. CCA has poor prognosis and a low survival rate due to the lack of early diagnosis methods and the limited effectiveness of current treatments. A number of oncogenic spliced-transcripts resulting from mRNA splicing errors have been reported in CCA, and aberrant mRNA splicing is suspected to be a key driver of this cancer type. The hyperphosphorylation of serine/arginine rich-splicing factors (SRSFs) by serine/arginine protein kinases (SRPKs) causes them to translocate to the nucleus where they facilitate gene splicing errors that generate cancer-related mRNA/protein isoforms. METHODS: The correlation between SRPK expression and the survival of CCA patients was analyzed using data from The Cancer Genome Atlas (TCGA) dataset. The effect of SRPK inhibitors (SRPIN340 and SPHINX31) on two CCA cell lines (KKU-213A and TFK-1) was also investigated. The induction of cell death was studied by Calcein-AM/PI staining, AnnexinV/7AAD staining, immunofluorescence (IF), and Western blotting (WB). The phosphorylation and nuclear translocation of SRSFs was tracked by WB and IF, and the repair of splicing errors was examined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). RESULTS: High levels of SRPK1 and SRPK2 transcripts, and in particular SRPK1, correlated with shorter survival in CCA patients. SRPIN340 and SPHINX31 increased the number of dead and apoptotic cells in a dose-dependent manner. CCA also showed diffuse expression of cytoplasmic cytochrome C and upregulation of cleaved caspase-3. Moreover, SRSFs showed low levels of phosphorylation, resulting in the accumulation of cytoplasmic SRSF1. To link these phenotypes with aberrant gene splicing, the apoptosis-associated genes Bridging Integrator 1 (BIN1), Myeloid cell leukemia factor 1 (MCL-1) and B-cell lymphoma 2 (BCL2) were selected for further investigation. Treatment with SRPIN340 and SPHINX31 decreased anti-apoptotic BIN1+12A and increased pro-apoptotic MCL-1S and BCL-xS. CONCLUSIONS: The SRPK inhibitors SRPIN340 and SPHINX31 can suppress the phosphorylation of SRSFs and their nuclear translocation, thereby producing BIN1, MCL-1 and BCL2 isoforms that favor apoptosis and facilitate CCA cell death.
Assuntos
Apoptose , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-bcl-2 , Fatores de Processamento de Serina-Arginina , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Apoptose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/antagonistas & inibidores , Fatores de Processamento de Serina-Arginina/genética , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Splicing de RNA/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Cancer stem cells (CSC) play an important role in carcinogenesis and are acknowledged to be responsible for chemoresistance in cholangiocarcinoma (CCA). Studying CCA CSC has been challenging, due to lack of consensus CSC markers, and to their plastic nature. Since dual expression of the core pluripotent factors SOX2/OCT4 has been shown to correlate with poor outcome in CCA patients, we selected the SOX2/OCT4 activating short half-life GFP-based live reporter (SORE6-dsCopGFP) to study CSC dynamics at the single-cell level. Transduction of five human CCA cell lines resulted in the expression of 1.8-13.1% GFP-positive (SORE6POS) cells. By live imaging, we found that SORE6POS CCA cells possess self-renewal capacity and that they can be induced to differentiate. Significantly, the SORE6POS cells were highly tumorigenic, both in vitro and in vivo, thus implicating the characteristics of primary CSCs. When we then analyzed for selected CSC-related markers, we found that the majority of both CD133+/CD44+, and CD133+/LGR5+ CCA cells were SORE6POS cells. Exposing transduced cells to standard CCA chemotherapy revealed higher growth rate inhibition at 50% (GR50s) for SORE6POS cells compared to GFP-negative (SORE6NEG) ones indicating that these CSC-like cells were more resistant to the treatment. Moreover, the chemotherapy induced SORE6POS from SORE6NEG cells, while retaining the existing SORE6POS population. Finally, treatment of transduced cells with CDK4/6 inhibitors in vitro for 3 days resulted in a lowered CSC number in the culture. Thus, applying a live reporter system allowed us to elucidate the stem cell diversity and drug-induced plasticity of CCA CSCs. These findings have clear implications for future management of such patients.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Células-Tronco Neoplásicas , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Genes Reporter , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB1/genética , Análise de Célula Única/métodos , Animais , Camundongos , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Antineoplásicos/farmacologia , Plasticidade Celular/efeitos dos fármacos , Resistencia a Medicamentos AntineoplásicosRESUMO
Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta-6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere-forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2-knockdown cells. The oxygen consumption ratio was also decreased in FADS2-depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy.
Assuntos
Apoptose , Neoplasias dos Ductos Biliares , Proliferação de Células , Colangiocarcinoma , Ácidos Graxos Dessaturases , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Humanos , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Dessaturases/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Animais , Linhagem Celular Tumoral , Camundongos , Movimento Celular , Ferroptose/genética , Triglicerídeos/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino , Ésteres do Colesterol/metabolismoRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is one of the most deadly cancers in the world. It usually has a bad prognosis and is challenging to identify in its early stages. Long noncoding RNAs (lncRNAs) have been shown in an increasing number of studies to be important in the control of signaling pathways, cell behaviors, and epigenetic modification that contribute to the growth of tumors. The purpose of this work was to examine the relationship between CCA and lncRNA AL161431.1. METHODS: Using TCGA clinical survival data, we evaluated the association between AL161431.1 expression and patient prognosis. Using the program cluster Profiler R, enrichment analysis was performed. Additionally, the association between immune cell infiltration and AL161431.1 expression was evaluated by a review of the TCGA database. Next, to ascertain if AL161431.1 influences tumor growth, migration, and invasion in CCA, functional in vitro assays were conducted. Quantitative real-time polymerase chain reaction (qPCR) was employed to gauge AL161431.1 expression levels in CCA cells. Western blot was used to measure protein levels. RESULTS: In CCA, AL161431.1 was extremely expressed. The patients in the high-risk group had a significantly poorer overall survival (OS) than the patients in the low-risk group. A more thorough look at the TCGA data showed a relationship between high expression levels of AL161431.1 and increased infiltration of T cells, T helper cells, and NK CD56dim cells. Furthermore, AL161431.1 knockdown in CCA cells impeded invasion, migration, and proliferation and also lowered the expression of phosphorylated Smad2/Smad3 to restrain the TGFß/SMAD signaling pathway. CONCLUSIONS: Our results indicate that the lncRNA AL161431.1 activates the TGFß/SMAD signaling pathway to enhance CCA development and metastasis. AL161431.1 could be a novel target for cholangiocarcinoma treatment or a diagnostic marker.
Assuntos
Neoplasias dos Ductos Biliares , Movimento Celular , Colangiocarcinoma , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Prognóstico , Feminino , Masculino , Invasividade NeoplásicaRESUMO
The incidence of intrahepatic cholangiocarcinoma (ICC) is steadily rising, and it is associated with a high mortality rate. Clinical samples were collected to detect the expression of HSPB8 and BAG3 in ICC tissues. ICC cells were cultured and transfected with plasmids that overexpressed or silenced specific genes to investigate the impact of gene expression alterations on cell function. qPCR and Western blot techniques were utilized to measure gene and protein expression levels. A wound healing assay was conducted to assess cell migration ability. The Transwell assay was used to assess cell invasion ability. Co-IP was used to verify the binding relationship between HSPB8 and BAG3. The effects of HSPB8 and BAG3 on lung metastasis of tumors in vivo were verified by constructing a metastatic tumor model. Through the above experiments, we discovered that the expressions of HSPB8 and BAG3 were up-regulated in ICC tissues and cells, and their expressions were positively correlated. The metastatic ability of ICC cells could be promoted or inhibited by upregulating or downregulating the expression of BAG3. Furthermore, the HSPB8-BAG3 chaperone complex resulted in the abnormal degradation of Filamin A by activating autophagy. Increased expression of Filamin A inhibits the migration and invasion of ICC cells. Overexpression of HSPB8 and BAG3 in vivo promoted the lung metastasis ability of ICC cells. The HSPB8-BAG3 chaperone complex promotes ICC cell migration and invasion by regulating CASA-mediated degradation of Filamin A, offering insights for enhancing ICC therapeutic strategies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Filaminas , Chaperonas Moleculares , Invasividade Neoplásica , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Humanos , Filaminas/metabolismo , Filaminas/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Animais , Camundongos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Movimento Celular , Linhagem Celular Tumoral , Masculino , Feminino , Camundongos Nus , Regulação Neoplásica da Expressão GênicaRESUMO
Drug resistance is a major challenge in the treatment of advanced cholangiocarcinoma (CCA). Understanding the mechanisms of drug resistance can aid in identifying novel prognostic biomarkers and therapeutic targets to improve treatment efficacy. This study established 5-fluorouracil- (5-FU) and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, and utilized comparative proteomics to identify differentially expressed proteins in drug-resistant cells compared to parental cells. Additionally, bioinformatics analyses were conducted to explore the biological and clinical significance of key proteins. The drug-resistant phenotypes of KKU-213FR and KKU-213GR cell lines were confirmed. In addition, these cells demonstrated increased migration and invasion abilities. Proteomics analysis identified 81 differentially expressed proteins in drug-resistant cells, primarily related to binding functions, biological regulation, and metabolic processes. Protein-protein interaction analysis revealed a highly interconnected network involving MET, LAMB1, ITGA3, NOTCH2, CDH2, and NDRG1. siRNA-mediated knockdown of these genes in drug-resistant cell lines attenuated cell migration and cell invasion abilities and increased sensitivity to 5-FU and gemcitabine. The mRNA expression of these genes is upregulated in CCA patient samples and is associated with poor prognosis in gastrointestinal cancers. Furthermore, the functions of these proteins are closely related to the epithelial-mesenchymal transition (EMT) pathway. These findings elucidate the potential molecular mechanisms underlying drug resistance and tumor progression in CCA, providing insights into potential therapeutic targets.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Biologia Computacional , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Gencitabina , Proteômica , Colangiocarcinoma/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Proteômica/métodos , Linhagem Celular Tumoral , Biologia Computacional/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Fluoruracila/farmacologia , Prognóstico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Movimento Celular/genética , Movimento Celular/efeitos dos fármacos , Mapas de Interação de Proteínas/genéticaRESUMO
The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.