RESUMEN
BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Osteonectina/metabolismo , Sorafenib/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The purpose of this study was to screen for changes in chemokine and chemokine-related genes that are expressed in hepatocellular carcinoma (HCC) as potential markers of HCC progression. Total RNA was extracted from tumor and peritumor tissues from mice with HCC and analyzed using a PCR microarray comprising 98 genes. Changes in gene expression of threefold or more were screened and subsequently confirmed by immunohistochemical analyses and western blotting. Furthermore, whether chemokine knockdown by RNA interference (RNAi) could significantly suppress tumor growth in vivo was also evaluated. Finally, total serum samples were collected from HCC patients with HBV/cirrhosis (n = 16) or liver cirrhosis (n = 16) and from healthy controls (n = 16). The serum mRNA and protein expression levels of CXCL1 in primary liver cancer patients were detected by qRT-PCR and western blot analysis, respectively. Several genes were up-regulated in tumor tissues during the progression period, including CXCL1, CXCL2, CXCL3, and IL-1ß, while CXCR1 expression was down-regulated. CBRH-7919 cells carrying CXCL1 siRNA resulted in decreased tumor growth in nude mice. The differences in serum CXCL1 mRNA and protein levels among the HCC, hepatic sclerosis (HS), and control groups were significant (P < 0.001). The mRNA and protein levels of CXCL1 in the HCC group were up-regulated compared with the HS group or the control group (P < 0.001). Several chemokine genes were identified that might play important roles in the tumor microenvironment of HCC. These results provide new insights into human HCC and may ultimately facilitate early HCC diagnosis and lead to the discovery of innovative therapeutic approaches for HCC.
Asunto(s)
Carcinoma Hepatocelular/genética , Quimiocinas/genética , Perfilación de la Expresión Génica/métodos , Interleucina-1beta/genética , Neoplasias Hepáticas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Quimiocinas/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-1beta/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Trasplante de NeoplasiasRESUMEN
Atypical teratoid/rhabdoid tumours (AT/RTs) are rare, highly malignant tumours of the central nervous system (CNS) with poor prognosis that usually affect young children. The aim of this study was to assess the clinicopathological features and prognostic factors of AT/RTs. Here, we describe the clinicopathological and immunohistochemical characteristics, along with the treatments and outcomes, of 22 patients with AT/RTs treated in our hospital from 2010 to 2015. Morphologically, cytoplasmic vacuoles, the most common characteristic in our cases, were observed in 68% of the cases. Similarly, vesicular nuclei were detected in 68% of the cases. However, rhabdoid cells were found in only 59.1% of the cases and were not observed in 40.9% of the cases. Immunohistochemical analysis revealed loss of nuclear INI1 expression in all 22 cases. Age, surgical resection and adjuvant therapy, but not tumour location, were associated with AT/RTs patient prognosis. Our results showed that cells with cytoplasmic vacuoles or with vesicular nuclei are more common than rhabdoid cells in patients with AT/RTs and that a lack of INI1 protein expression is the most useful marker for the differential diagnosis of AT/RTs. Young age is a negative prognostic factor, whereas gross total surgical resection and adjuvant therapy are positive prognostic factors for AT/RT patients.
Asunto(s)
Neoplasias Encefálicas/patología , Tumor Rabdoide/patología , Teratoma/patología , Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , China , Femenino , Humanos , Inmunohistoquímica , Lactante , Estimación de Kaplan-Meier , Masculino , Pronóstico , Tumor Rabdoide/mortalidad , Proteína SMARCB1/biosíntesis , Teratoma/mortalidadRESUMEN
OBJECT The purpose of this study was to explore the clinical features and outcome of medulloblastoma in Chinese children. The authors analyze the reasons that treatment is abandoned and attempt to provide evidence-based recommendations for improving the prognosis of medulloblastoma in this population. METHODS A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in this study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients' median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months). RESULTS At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p < 0.001), older age (≥ 3 years) at diagnosis (p = 0.010), gross-total resection (p = 0.012), annual family income higher than $3000 (p = 0.033), and living in urban areas (p = 0.008) were favorable prognostic factors. Multivariate analysis revealed that postoperative RT combined with chemotherapy was an independent prognostic factor (p < 0.001). The treatment abandonment rate in this cohort was 31% (21 of 67 cases). CONCLUSIONS There was a large gap between the outcome of medulloblastoma in Chinese children and the outcome in Western children. Based on our data, treatment abandonment was the major cause of therapeutic failure. Parents' misunderstanding of medulloblastoma played a major role in abandonment, followed by financial and transportation difficulties. Establishment of multidisciplinary treatment teams could improve the prognosis of medulloblastoma in Chinese children.