RESUMEN

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/ß-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/ß-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/ß-catenin pathway with the CBP/ß-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and ß-catenin while upregulating GSK-3ß expression. The interaction between Hh/GLI1 and Wnt/ß-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of ß-catenin and decreased the inhibition of GSK-3ß in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/ß-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

Asunto(s)

Proteínas Hedgehog , Linfoma de Células del Manto , Vía de Señalización Wnt , Proteína con Dedos de Zinc GLI1 , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Humanos , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/antagonistas & inhibidores , Proteína con Dedos de Zinc GLI1/genética , Proteínas Hedgehog/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Línea Celular Tumoral , Piridinas/farmacología , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proliferación Celular/efectos de los fármacos , beta Catenina/metabolismo , Pirimidinas , Pirimidinonas

RESUMEN

The long non-coding RNA HOTAIR and the Hedgehog-Gli1 signaling pathway are closely associated with tumor occurrence and drug resistance in various cancers. However, their specific roles in the development of EGFR-TKIs resistance in non-small cell carcinoma remain unclear. To address the issue of EGFR-TKIs resistance, this study utilized the electrospray method to prepare sodium alginate microspheres encapsulating HOTAIR siRNA (SA/HOTAIR siRNA) and investigated its effects on RNA interference (RNAi) in the gefitinib-resistant cell line PC9/GR. Furthermore, the study explored whether HOTAIR could modulate EGFR-TKIs resistance through the Hedgehog-GLi1 signaling pathway. The experimental results showed that sodium alginate (SA) microspheres demonstrated excellent biocompatibility with high encapsulation efficiency and drug-loading capacity, effectively enhancing the silencing efficiency of siRNA. HOTAIR siRNA significantly inhibited the proliferation, migration, and invasion abilities of PC9/GR cells while promoting apoptosis. Additionally, HOTAIR siRNA effectively suppressed tumor growth and downregulated the Hedgehog-GLi1 pathway and anti-apoptotic proteins, which were confirmed in animal experiments. Moreover, SA/HOTAIR siRNA exhibited superior inhibition of cellular and tumor functions compared to using HOTAIR siRNA alone. Clinical research findings indicated that monitoring the expression level of HOTAIR in the serum and urine samples of NSCLC patients before and after receiving EGFR-TKIs treatment can predict the efficacy of EGFR-TKIs to a certain extent. This study provided evidence that HOTAIR siRNA effectively mitigated the development of acquired resistance to EGFR-TKIs by inhibiting the Hedgehog-GLi1 pathway. Furthermore, it introduced a reliable and long-lasting drug delivery system for combating acquired resistance to EGFR-TKIs.

Asunto(s)

Neoplasias Pulmonares , ARN Largo no Codificante , Animales , Humanos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Hedgehog/genética , Proteínas Hedgehog/farmacología , Proteínas Hedgehog/uso terapéutico , Receptores ErbB/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/farmacología , Microesferas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Alginatos/farmacología

RESUMEN

Objective: Insensitivity to radiotherapy accounts for the majority of therapeutic failures in cervical cancer (CC) patients who undergo radical radiotherapy. We aimed to elucidate the molecular mechanisms underlying radiosensitivity to identify methods to improve the overall 5-year survival rate. The atypical protein kinase C iota (aPKCι) gene PRKCI exhibits tumor-specific copy number amplification (CNA) in CC. We investigated how PRKCI decreases radiosensitivity in CC and assessed the interplay between PRKCI and the Hedgehog (Hh)/GLI1 pathway in the present research. Methods: The biological functions of PRKCI in CC radiosensitivity were explored through immunohistochemistry, colony formation, Cell Counting Kit-8 (CCK-8), cell cycle, apoptosis assays, and xenograft models. qRT-PCR, Western blotting analysis, and immunofluorescence assays were utilized to evaluate the interplay between PRKCI and the Hh/GLI1 pathway and its mechanism in PRKCI-decreased radiosensitivity in CC. Furthermore, the effect of auranofin (AF), a selective inhibitor of PKCι, on CC cells was explored through biochemical assays in vitro and in vivo. Results: We found that high PRKCI expression was responsible for decreased survival in CC. PRKCI was intimately associated with radiation-triggered alterations in proliferation, the cell cycle, apoptosis, and xenograft growth. The Hh/GLI1 pathway was activated when PRKCI expression was altered. PRKCI functions downstream of the Hh/GLI1 pathway to phosphorylate and activate the transcription factor GLI1. AF acts as a radiosensitizer and showed biological effects in vitro and in vivo. Conclusions: PRKCI is a therapeutic target for regulating radiosensitivity in CC. This molecule regulates radiosensitivity by modulating GLI1 relocalization and phosphorylation in CC via the Hh/GLI1 pathway.

RESUMEN

R-spondins 2 (RSPO2) protein is a member of RSPO family which plays an essential role in stem cell survival, development and tumorigenicity. There has several evidence suggested that RSPO2 involved in breast, gastric, liver and colorectal cancer. However, the specific function and mechanism of RSPO2 in nasopharyngeal carcinoma (NPC) remain unknown. In the present study, we first observed that RSPO2 expression was elevated in NPC cell lines SUNE-6-10B, SUNE-5-8F, and CNE-1 compared with the normal laryngeal epithelia cell line NP69. Knockdown of RSPO2 significantly inhibits SUNE-6-10B and CNE-1 cell survival and proliferation by using CCK-8 assay and Edu assay, respectively. Further studies verified that RSPO2 silence suppressed migration and invasion of SUNE-6-10B and CNE-1 cells. Further studies suggested that RSPO2 silence suppressed epithelial-to-mesenchymal transition (EMT) related protein E-cadherin expression and promoted Vimentin and N-cadherin expression both in SUNE-6-10B and CNE-1 cells. Molecular mechanism explorations showed that RSPO2 deletion increased ZNRF3 expression and inhibited Gli1 expression. Additionally, knockdown ZNRF3 expression or overexpression Gli1 both reversed the effects of RSPO2 silence on NPC growth and metastasis. Finally, RSPO2 depletion was impaired NPC tumor growth in vivo animal experiments. In conclusion, the present study confirmed that RSPO2 silence inhibits the tumorigenesis of NPC via ZNRF3/Hedgehog-Gli1 signal pathway.

Asunto(s)

Carcinogénesis/metabolismo , Silenciador del Gen , Proteínas Hedgehog/metabolismo , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismo , Proteína con Dedos de Zinc GLI1/metabolismo , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Ubiquitina-Proteína Ligasas/genética , Proteína con Dedos de Zinc GLI1/genética

RESUMEN

Aberrant activation of Hedgehog-Gli1 signaling and accumulation of Gli1 in hepatocellular carcinoma (HCC) are frequently observed. However, the mechanisms leading to the overactivation of this signaling pathway are not fully understood. In this study, we show that the short isoform of PHD finger protein 19 (PHF19) interacts with ß-TrCP, the E3 ligase of Gli1, and that knocking down PHF19 promotes the ubiquitination of Gli1. In a biological function study, PHF19 was found to promote the growth of HCC cells both in liquid culture and in soft agar. Moreover, knocking out PHF19 in a HCC mouse model (MycF/F) using the hydrodynamic method inhibited tumorigenesis and improved survival. Taken together, these results demonstrate that PHF19 promotes the growth of HCC cells by activating the Hedgehog signaling pathway.

Asunto(s)

Carcinoma Hepatocelular/genética , Proteínas de Unión al ADN/genética , Proteínas Hedgehog/genética , Neoplasias Hepáticas/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Proteína con Dedos de Zinc GLI1/genética , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/metabolismo , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Procesamiento Proteico-Postraduccional , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Análisis de Supervivencia , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Carga Tumoral , Ubiquitinación , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína con Dedos de Zinc GLI1/metabolismo

RESUMEN

Micro/nanotextured topographies (MNTs) can modulate cell-biomaterial interactions mostly by their controllable geometrics. Among them, TiO2 nanotubes, regarded as having a highly controllable nanoscale geometry, have been extensively investigated and applied and significantly affect diameter-dependent cell biological behaviors. In this study, we used five typical MNTs decorated with TiO2 nanotubes with diameters of 30, 50, 70, 100 and 120 nm to explore the optimal nanotube diameter for improving the biofunctional properties and to more deeply understand the underlying mechanisms by which these MNTs affect osteogenic differentiation by revealing the effect of beta1-integrin/Hedgehog-Gli1 signaling on this process. The MNTs affected MG63 osteoblast-like cell spreading, osteogenic gene expression (BMP-2, Runx2 and ALP), mineralization and ALP activity in a diameter-dependent pattern, and the optimal TiO2 nanotube diameter of 70 nm provided the best microenvironment for osteogenic differentiation as well as beta1-integrin/Hedgehog-Gli1 signaling activation. This enhanced osteogenic differentiation by the optimal-diameter TiO2 nanotubes of 70 nm was attenuated via suppression of the beta1-integrin/ Hedgehog-Gli1 signaling, which indicated a significant role of this pathway in mediating the diameter-dependent osteogenic differentiation promotional effect of MNTs with different TiO2 nanotube diameters. These results might provide deeper insights into the signal transduction mechanisms by which different nanoscale geometries influence cellular functions for biomaterial modification and biofunctionalization.

Asunto(s)

Proteínas Hedgehog/metabolismo , Integrina beta1/metabolismo , Nanotubos/química , Osteoblastos/citología , Osteogénesis , Titanio/química , Proteína con Dedos de Zinc GLI1/metabolismo , Diferenciación Celular , Proliferación Celular , Proteínas Hedgehog/genética , Humanos , Integrina beta1/genética , Osteoblastos/metabolismo , Propiedades de Superficie , Proteína con Dedos de Zinc GLI1/genética

RESUMEN

OBJECTIVE: To investigate how the interaction of CtBP2 with ZBTB18 affect glioblastoma (GBM). METHODS: Western blotting was performed to detect CtBP2 and ZBTB18 expression in GBM and normal brain tissues (NBT). U-87 MG cells were transfected with ZBTB18 CRISPR activation plasmid, CtBP2 shRNA with/without ZBTB18 shRNA. The biological characteristics were detected by EdU assay, MTT, Wound-healing, Transwell, TUNEL staining, and Flow cytometry. Furthermore, U-87 MG cells transfected with CtBP2 shRNA and/or ZBTB18 shRNA were injected into the flank region of mice and the tumor volume was measured. The mRNA and protein expression was quantified by qRT-PCR or Western blotting. RESULTS: GBM tissues exhibited increased CtBP2 expression and decreased ZBTB18 expression, which demonstrated a negative correlation in GBM tissues and showed the combined effect on prognosis. Based on immunoprecipitation and immunofluorescence, there was an interaction between CtBP2 and ZBTB18 in U-87 MG cells. CtBP2 shRNA counteracted the effect of ZBTB18 shRNA on inhibiting U-87 MG cell apoptosis, as well as promoting cell proliferation and viability with increased EMT, invasion and migration. Meanwhile, CtBP2 shRNA interact with ZBTB18 to block cells at phase G0/G1 and suppress SHH-GLI1 pathway. CtBP2 shRNA decreased tumor volume, increase ZBTB18 expression in tumor tissues, and inhibit SHH-GLI1 pathway in mice, which could be reversed by ZBTB18 shRNA. CONCLUSION: CtBP2 elevation and ZBTB18 down-regulation were found in GBM, both of which were associated with prognosis of GBM patients. CtBP2 interacted with ZBTB18 to affect biological characteristics of GBM cells, and the tumor growth, which may be related to the SHH-GLI1 pathway.

Asunto(s)

Oxidorreductasas de Alcohol/genética , Neoplasias Encefálicas/patología , Proteínas Co-Represoras/genética , Glioblastoma/patología , Proteínas Represoras/genética , Animales , Apoptosis/genética , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Humanos , Ratones , Invasividad Neoplásica/genética , Pronóstico , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Trichosanthes kirilowii, which is a type of Liana from cucurbitaceous family, possesses many bioactive constituents and therefore has multifarious pharmacological functions. TKP, which is a serine protease extracted from the fruit of Trichosanthes kirilowii, has been reported to possess potential anticancer activity. However, the effects of TKP on cancer cell migration and invasion are still unknown. Here, we reported that TKP could inhibit the migration and invasion abilities of colorectal cancer cells. In addition, the mRNA, protein expression levels, and activities of migration and invasion-related proteins MMP2 and MMP9 were decreased in TKP-treated cells. Mechanistically, TKP treatment repressed Wnt/ß-catenin and Hedgehog/Gli1 signaling cascades. However, the addition of lithium chloride or the transfection of plasmid pcDNA3.1-V5-HisA-Gli1 reversed the impacts of TKP on MMP2, MMP9, cell migration, and invasion. These results indicated that TKP suppressed the migration and invasion of colorectal cancer cells through blocking Wnt/ß-catenin and Hedgehog/Gli1 pathways-mediated MMP2 and MMP9.

Asunto(s)

Adenocarcinoma/patología , Antineoplásicos Fitogénicos/farmacología , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Serina Proteasas/farmacología , Trichosanthes/química , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Proteínas Hedgehog/metabolismo , Humanos , Invasividad Neoplásica , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Serina Proteasas/aislamiento & purificación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Trichosanthes/enzimología , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/genética , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo , beta Catenina/metabolismo

RESUMEN

Osteoarthritis (OA) is characterized by articular cartilage degradation and joint inflammation. The purpose of the present study is to elucidate the role of the specific function of PRMT1 in chondrocytes and its association with the pathophysiology of OA. We observed that the expression of PRMT1 was apparently upregulated in OA cartilage, as well as in chondrocytes stimulated with IL-1ß. Additionally, knockdown of PRMT1 suppressed interleukin 1 beta (IL-1ß)-induced extracellular matrix (ECM) metabolic imbalance by regulating the expression of MMP-13, ADAMTS-5, COL2A1, and ACAN. Furthermore, silencing of PRMT1 dramatically declined the production of prostaglandin E2 (PGE2) and nitric oxide as well as the level of pro-inflammatory cytokine IL-6 and TNF-α. Mechanistic analyses further revealed that IL-1ß-induced activation of the Hedgehog/Gli-1 signaling is suppressed upon PRMT1 knockdown. However, the effects of inhibition of PRMT1-mediated IL-1ß-induced cartilage matrix degradation and inflammatory response in OA chondrocytes were obviously abolished by Hedgehog agonist Purmorphamine (Pur). Our data collectively suggest that silencing of PRMT1 exerts anti-catabolic and anti-inflammatory effects on IL-1ß-induced chondrocytes via suppressing the Gli-1 mediated Hedgehog signaling pathway, indicating that PRMT1 plays a critical role in OA development and serves as a promising therapeutic target for OA.

Asunto(s)

Cartílago/metabolismo , Condrocitos/metabolismo , Técnicas de Silenciamiento del Gen , Proteínas Hedgehog/metabolismo , Interleucina-1beta/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Represoras/genética , Transducción de Señal , Proteína con Dedos de Zinc GLI1/metabolismo , Cartílago/patología , Condrocitos/patología , Proteínas Hedgehog/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/metabolismo , Proteína con Dedos de Zinc GLI1/genética

RESUMEN

Hedgehog-Gli1 signaling is evolutionarily conserved and plays an essential role in osteoblast proliferation and differentiation as well as bone formation. To evaluate the role of the Hedgehog-Gli1 pathway in the response of osteoblasts to hierarchical biomaterial topographies, human MG63 osteoblasts were seeded onto smooth, microstructured, and micro-/nanotextured topography (MNT) titanium to assess osteoblast proliferation and differentiation in terms of proliferative activity, alkaline phosphatase (ALP) production, and osteogenesis-related gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Sonic hedgehog (Shh), Smoothened (Smo), and Gli1, and the protein levels were assayed by Western blotting. MG63 cells treated with the Smo inhibitor cyclopamine were seeded onto the titanium specimens, and the cell proliferation and differentiation were studied in the presence or absence of cyclopamine. Our results showed that compared to the smooth and microstructured surfaces, the MNTs induced a higher gene expression and protein production of Shh, Smo, and Gli1 as well as the activation of Hedgehog signaling. The enhanced proliferative activity, ALP production, and expression of the osteogenesis-related genes (bone morphogenetic protein-2, ALP, and runt-related transcription factor 2) enabled by the MNTs were significantly downregulated by the presence of cyclopamine to a similar level as those on the smooth and acid-etched microstructured surfaces in the absence of cyclopamine. This evidence explicitly demonstrates pivotal roles of Hedgehog-Gli1 signaling pathway in mediating the enhanced effect of MNTs on MG63 proliferation and differentiation, which greatly advances our understanding of the mechanism involved in the biological responsiveness of biomaterial topographies. These findings may aid in the optimization of hierarchical biomaterial topographies targeting Hedgehog-Gli1 signaling.

Asunto(s)

Técnicas de Cultivo de Célula/instrumentación , Proteínas Hedgehog/metabolismo , Osteoblastos/citología , Proteína con Dedos de Zinc GLI1/metabolismo , Fosfatasa Alcalina/metabolismo , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Proteínas Hedgehog/genética , Humanos , Nanoestructuras/química , Nanotubos/química , Osteoblastos/fisiología , Osteogénesis/fisiología , Transducción de Señal/efectos de los fármacos , Receptor Smoothened/antagonistas & inhibidores , Receptor Smoothened/metabolismo , Propiedades de Superficie , Titanio/química , Alcaloides de Veratrum/farmacología

RESUMEN

Gli1 is an important signaling molecular in Hedgehog signaling pathway. In our study, we explored the adjustment effect of Hedgehog-Gli1 signaling pathway on chicken male germ cells differentiation based on the transcriptome-wide analyses of chicken ESCs, primordial germ cells (PGCs) and spermatogonia stem cells (SSCs) that were associated with male germ cell differentiation. We screened out Hedgehog signaling pathway and identified 8 candidated differentially expressed genes (DEGs), Wnt3a, Wnt16, Wnt8a, HHIPL1, Gli1, BMP6, BMP7 and TTLL4. These DEGs expression change trend among blastoderm, genital ridge and testes, from which ESCs, PGCs and SSCs were isolated was the same as RNA-Seq data with quantitative RT-PCR evaluation. Based on retinoic acid (RA) induction of ESCs to SSCs in vitro, Gli1 overexpression has the ability to induce ESCs differentiation and SSCs-like cells formation and high expression of related reproductive genes, like Cvh, C-kit, Blamp1, Prmd14, Stra8, Dazl, integrin α6 and integrin ß1 and so on in vitro. While RNAi knockdown of Gli1 can protect ESCs from differentiating into SSCs and correspondingly reduce the expression of the associated reproductive gene in vivo and vitro. Immunochemistry results showed that Gli1 overexpression could increase the expression of PGCs markers Cvh and C-kit and SSCs markers integrin α6 and integrin ß1 in vivo, while Gli1 knockdown can have the opposite effect in vivo and in vitro. PAS stain and flow cytometry (FCM) evaluation results indicated the quantity of germ cells is decrease or increase with Gli1 knockdown or overexpression. Collectively, these results uncovered a novel function of Gli1 and demonstrated Hedgehog-Gli1 signaling pathway involved in chicken male germ cell differentiation, where it acts as a facilitator.

Asunto(s)

Embrión de Pollo/citología , Regulación del Desarrollo de la Expresión Génica/fisiología , Células Germinativas/fisiología , Proteínas Hedgehog/metabolismo , Células Madre/fisiología , Proteína con Dedos de Zinc GLI1/metabolismo , Animales , Diferenciación Celular/fisiología , Proteínas Hedgehog/genética , Masculino , Proteína con Dedos de Zinc GLI1/genética

RESUMEN

Breast cancer is the most prominent cause of cancer death in women worldwide. The highlights of this review are to provide an overview of the targeted therapeutic agents, challenges with metastatic breast cancer (MBCa), mechanisms of action through Hedgehog/Gli 1 signaling pathway and future prospective. Over a decade of success, several drugs have been approved and are in the advanced stages of clinical trials that target the receptors such as estrogen receptor, growth factor receptor, receptor activator of nuclear factor kappa-B, etc. Currently, several monoclonal antibodies are also used for the treatment of breast cancer. Advances in understanding tumor biology, particularly signaling pathways such as Notch signaling pathway, Hedgehog/Gli 1 signaling pathway, and inhibitors are considered to be important for bone metastasis. These studies may provide vital information for the design and development of new strategies with respect to efficacy, reduction of the side effects, and treatment strategies.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Proteínas Hedgehog/metabolismo , Humanos , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Receptores de Estrógenos/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína con Dedos de Zinc GLI1/metabolismo

RESUMEN

OBJECTIVES: The study aimed to investigate the effects of resveratrol on colorectal cancer HCT116 cells, including cell viability, apoptosis, and migration, and the partial mechanisms focused on hedgehog/gli-1 signaling pathways. MATERIALS AND METHODS: We chose the appropriate time and concentration of recombinant human Sonic hedgehog (Shh) stimulation by cell viability. The proportion of cell apoptosis was detected by flow cytometry; HCT116 cell migration was measured by scratch test; the expression of Ptch, Smo, and Gli-1 was measured by Western blot analysis. RESULTS: Shh signaling increased HCT116 cell viability and migration, inhibited cell apoptosis, and upregulated the expression of Ptch, Smo, and Gli-1. Resveratrol obviously inhibited HCT116 cell viability and migration, promoted cell apoptosis, and suppressed the protein of Ptch, Smo, and Gli-1. Furthermore, the effects of resveratrol and Shh on human colorectal cancer HCT116 cells were in a dose- and time-dependent manner. CONCLUSION: The inhibitory effect of resveratrol on HCT116 cells may be mediated by hedgehog/gli-1 signaling pathways.

RESUMEN

Alteration of metabolic profile is one of the hallmarks of cancer cells. Statin, the inhibitors for synthesis of cholesterol, has shown anti-cancer effects on the gastric cancer cells. However, the functions of its target, HMGCR, in the progression of gastric cancer remain unknown. In the present study, we investigated the expression profile and the biological functions of HMGCR in gastric cancer. It was found that the expression of HMGCR was increased in gastric cancer tissues. Over-expression of HMGCR promoted the growth and migration of gastric cancer cells, while knocking down the expression of HMGCR inhibited the growth, migration and tumorigenesis of gastric cancer cells. In the further molecular mechanism study, HMGCR was shown to activate Hedgehog/Gli1 signaling and promoted the expression of Gli1 target genes. Taken together, this study demonstrated the tumor-promoting effects of HMGCR in gastric cancer and suggested HMGCR as a promising therapeutic target.

Asunto(s)

Hidroximetilglutaril-CoA Reductasas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Animales , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Ratones Desnudos , Transducción de Señal , Neoplasias Gástricas/metabolismo , Transcriptoma , Regulación hacia Arriba