HBO1 overexpression is important for hepatocellular carcinoma cell growth.
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ABSTRACT:
SUBMITTER: Zhong W
PROVIDER: S-EPMC8155027 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (score<or=1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score >or=2 (mean+/-s.d.: 2%+/-2.4 vs 7.5%+/-10.3, P<0.05). Squamous cell carcinoma antigen mRNA could be directly sequenced in 14 out of 18 liver tumours but in none of the corresponding nontumour samples. From sequence alignment, a novel SCCA1 variant (G(351) to A) was identified in five cases, while SCCA1 was revealed in six cases and SCCA2 in three cases. In conclusion, SCCA variants are overexpressed in HCC, independently of tumour aetiology. A novel SCCA1 variant has been identified in one third of liver tumours.
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Project description:Galectin-4 is a member of multifunctional galactoside-binding lectin family with various biological functions, including tumor cells proliferation, cancer progression, cell adhesion, and tumor metastasis. In this study, we aimed to investigate the putative function of galectin-4 in tumor progression of hepatocellular carcinoma (HCC), and explore the possible mechanisms of galectin-4 related biological pathway. The result showed that the galectin-4 was significantly up-regulated in HCC tissues/cell lines compared to matched peritumor tissues/a normal liver cell line, respectively. Furthermore, overexpressing galectin-4 in HCCLM3 cells led to promotion of cell proliferation and inhibition of cell apoptosis via up-regulation of Cyclin D1, down-regulation of p21 and decreased pro-apoptotic Bax/Bcl-2 ratio, But knockdown of galectin-4 reversed these properties. Furthermore, galectin-4 could promote cell-cell adhesion via stabilizing the adherens junction complexes. These observations was further validated in the xenograft animal model. Taken together, galectin-4 plays an important role in HCC progression.
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Project description:Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis.
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Project description:Hepatocellular carcinoma (HCC), one of the most common and lethal cancers worldwide, has a high recurrence rate with current treatment modalities. Identifying biomarkers for early diagnosis and discovering new sufficient molecular targets for the development of targeted therapies are urgently needed. RAB10, a member of the RAS family, has been shown to be highly expressed in HCC. However, the function of RAB10 in HCC is less studied. Here we report that RAB10 acts as an oncogene in HCC. The shRNA-mediated knockdown of RAB10 significantly reduced the proliferation of HCC cells and colony formation, induced cell cycle arrest at G0/G1 phase and increased apoptosis in vitro. In addition, RAB10 knockdown suppressed HCC growth in nude mice. Moreover, RAB10 silencing decreased the phosphorylation of InsR, Met/HGFR, Ron/MST1R, Ret, c-Kit/SCFR, EphA3, EphB4, Tyro3/Dtk, Axl, Tie2/TEK, VEGFR2/KDR, Akt/PKB/Rac, S6 Ribosomal Protein and c-Abl, while the phosphorylation of HSP27, p38 MAPK, Chk2 and TAK1 increased significantly. These results suggest that RAB10 regulates cell survival and proliferation through multiple oncogenic, cell stress and apoptosis pathways. More importantly, high RAB10 expression levels in HCC cells correlated with a poor prognosis in HCC patients. Therefore, our findings revealed an oncogenic role for RAB10 in the pathogenesis of HCC and that RAB10 is a potential molecular target or a biomarker for HCC.
| S-EPMC5432270 | biostudies-literature
Project description:BackgroundOur previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC).Aim of the studyThis study aimed to clarify the effect of CCNB2 gene silencing on tumorigenesis in nude mice and to detect the potential mechanism.MethodsThe effect of CCNB2 on HCC was tested in vivo. The downstream target genes of CCNB2 were predicted by proteomics and confirmed by western blot assay. The regulatory functions of CCNB2 in the proliferation and migration of HCC cells were determined through functional recovery experiments. The expression of the downstream target genes of CCNB2 was detected by immunohistochemistry.ResultsKnockdown of CCNB2 decreased tumour formation rate and tumour volume and weight and inhibited tumour proliferation. A total of 130 differentially expressed proteins were detected by proteomics, and Jagged 1 (JAG1) was predicted as the potential downstream target of CCNB2. Western blot assay revealed that CCNB2 and JAG1 expression was significantly correlated in HCC cells. The results of functional recovery experiments suggested that CCNB2 knockdown weakened the proliferation and migration ability of HCC cells, while JAG1 overexpression restored this ability of HCC cells that was weakened by CCNB2 knockdown. Immunohistochemistry showed that JAG1 expression was higher in HCC tissues than in paracancerous tissues and was related to tumour size and number and tumour thrombus formation.ConclusionsThe proliferation of HCC cells in vivo was inhibited by CCNB2 knockdown. CCNB2 may accelerate the proliferation and metastasis of HCC cells by increasing JAG1 expression.
| S-EPMC9004552 | biostudies-literature
Project description:CR6-interacting factor 1 (Crif1) is a mitochondrial protein which is required for the assembly of oxidative phosphorylation (OXPHOS) complexes. Our bioinformatics analysis based on Cancer Genome Atlas (TCGA) database revealed an aberrant overexpression of CRIF1 in hepatocellular carcinoma (HCC). However, the clinical significance and biological functions of CRIF1 are still unclear in this malignancy. Here, we report that CRIF1 is frequently overexpressed in HCC cells mainly due to the downregulation of miR-497-5p, which is associated with poor prognosis of patients with HCC. CRIF1-promoted HCC growth and metastasis by suppressing cell apoptosis and inducing cell cycle progression and epithelial to mesenchymal transition (EMT). Mechanistically, increased mitochondrial ROS production and consequently activation of the NFκB signaling pathway was found to be involved in the promotion of growth and metastasis by CRIF1 in HCC cells. In summary, CRIF1 plays an oncogenic role in HCC progression through activating ROS/NFKB pathway, implying CRIF1 as a potential prognostic factor and therapeutic target in HCC.
| S-EPMC7205899 | biostudies-literature
Project description:BackgroundHuman MTP18 (mitochondrial protein 18?kDa) is a novel nuclear-encoded mitochondrial membrane protein that is involved in controlling mitochondrial fission. Our bioinformatic analysis of TCGA data revealed an aberrant overexpression of MTP18 in hepatocellular carcinoma (HCC). We analyzed its biological effects and prognostic significance in this malignancy.MethodsMTP18 expression was evaluated by qRT-PCR and western blot analysis in 20 paired tumor and peritumor tissues. Clinical impact of MTP18 overexpression was assessed in 156 patients with HCC. The effects of MTP18 knockdown or overexpression on cell growth and metastasis were determined by cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion assays. Furthermore, the underlying molecular mechanisms by which MTP18 overexpression promoted HCC cell growth and metastasis were explored.ResultsMTP18 was commonly overexpressed in HCC tissues mainly due to the downregulation of miR-125b, which significantly contributed to poor prognosis of HCC patients. Functional experiments revealed that MTP18 promoted both the growth and metastasis of HCC cells by inducing the progression of cell cycle, epithelial to mesenchymal transition (EMT) and production of MMP-9, and suppressing cell apoptosis. Mechanistically, increased mitochondrial fission and subsequent ROS production was found to be involved in the promotion of growth and metastasis by MTP18 in HCC cells.ConclusionsMTP18 plays a pivotal oncogenic role in hepatocellular carcinogenesis; its overexpression may serve as a novel prognostic factor and a therapeutic target in HCC.
| S-EPMC6148245 | biostudies-literature
Project description:Furin is a member of the pro-protein convertase family. It processes several growth regulatory proteins into their active forms, which are critical to tumor progression, metastasis, and angiogenesis. Furin over-expression could occur in liver cancer and a previous study showed that over-expression of furin promoted HepG2 cell invasion in tail vein xenograft models. However, the clinical relevance of furin expression in hepatocellular carcinoma (HCC) remained unknown. Surprisingly, in a postoperative survival analysis for HCC patients, it was found that the tumor/non-tumor (T/N) ratio of furin expression ? 3.5 in HCC tissues predicted a better postoperative disease-free survival (DFS) (P = 0.010; log-rank test). Furthermore, subcutaneous xenograft experiments demonstrated a significant suppression effect of tumor growth in the furin-overexpressed xenografts (Huh7-Furin) compared to the mock control. Administration of a synthetic furin inhibitor for inhibition of the pro-protein convertase activity, decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decRVKR-CMK), to the Huh7-Furin xenograft bearing mice restored the repression effect of tumor growth. In contrast, administration of decRVKR-CMK to the mock Huh7 xenograft bearing mice showed no change in growth rate. In conclusion, furin overexpression inhibited HCC tumor growth in a subcutaneous xenograft model and predicted a better postoperative DFS in clinical analysis.
| S-EPMC3393699 | biostudies-literature
Project description:Background: Accumulating studies manifest that BTB and CNC homology 1 (BACH1) facilitates multiple malignancies progression and metastasis, and targeting the BACH1 pathway enhances antitumor efficacy. Nevertheless, the exact mechanism of BACH1 promoting growth and metastasis and its therapeutic significance in hepatocellular carcinoma (HCC) remain unclear. Methods: The expression of BACH1 in human HCC specimens and HCC cell lines was analyzed by quantitative RT-PCR (RT-qPCR), western blot, and immunohistochemistry (IHC). The invasiveness and metastasis of HCC cells in vitro and in vivo were evaluated using transwell assays and orthotopic xenograft models. The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to explore the transcriptional regulation of insulin-like growth factor 1 receptor (IGF1R) and protein tyrosine kinase 2 (PTK2) by BACH1. Results: BACH1 was prominently upregulated in human HCC samples and elevated BACH1 expression was associated with poor overall survival (OS) and high recurrence rates of HCC patients. BACH1 facilitated growth and metastasis of HCC by upregulating cell motility-related genes IGF1R and PTK2. Notably, insulin-like growth factor 2 (IGF2), the ligand of IGF1R, in turn upregulated BACH1 expression through the IGF1R-ERK1/2-ETS1 cascades, thus forming a positive feedback loop to provoke HCC growth and metastasis. Moreover, combining IGF1R inhibitor linsitinib with PTK2 inhibitor defactinib prominently suppressed BACH1-mediated HCC growth and metastasis. Conclusions: These results demonstrated the tumorigenic and pro-metastatic role of BACH1 in HCC, which could be a promising biomarker for predicting poor prognosis and selecting patients who could benefit from combination therapy of IGF1R-targeted and PTK2-directed.
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Project description:Cumulative evidence has indicated that mitochondrial respiration dysfunction plays important roles in tumorigenesis. However, the role of COX7RP, a critical regulator in the formation of mitochondrial respiratory supercomplex that has been suggested to be over-expressed in hepatocellular carcinoma (HCC) by our bioinformatic analysis of TCGA data, in tumor progression remains largely unclear. In this study, we found that COX7RP is frequently over-expressed in HCC mainly due to the down-regulation of miR-130a-3p and predicts poor prognosis of HCC patients. Functional experiments revealed that COX7RP promoted both growth and metastasis of HCC through induction of cell cycle progression and epithelial to mesenchymal transition (EMT), and suppression of cell apoptosis. Mechanistically, increased generation of reactive oxygen species (ROS) and subsequently activated nuclear transcription factor-κB (NF-κB) signaling was found to contribute to the promotion of HCC cell growth and metastasis by COX7RP. Collectively, COX7RP plays a critical oncogenic role in hepatocellular carcinogenesis, supporting COX7RP as a novel prognostic factor and therapeutic target in HCC.
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