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Derlin-1 Promotes the Progression of Human Hepatocellular Carcinoma via the Activation of AKT Pathway.

ABSTRACT: Introduction:Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. In the present research, we explored a new oncogene, derlin-1 (DERL1), and studied its role and mechanism in human HCC. Methods:We assessed the expression and prognosis value of DERL1 in human HCC by using GEPIA dataset analysis and immunohistochemistry. To elucidate the specific function of DERL1, we suppressed its expression in two HCC cell lines, HuH7 and Hep3B, and overexpressed DERL1 in Hep3B cells. Cell proliferation and migration was detected by CCK8 and transwell assays. Cell flow cytometry was used to evaluate cell apoptosis. Results:Our results demonstrated that DERL1 was highly expressed in HCC samples (n = 369) than in normal samples (n = 160). Similar results were obtained in 60 clinical samples that we collected from the local hospital. The high expression rate of DERL1 reached 78.3% (47/60). DERL1 overexpression samples were concentrated in patients with tumor diameters >5cm or lymph node metastases. Thus, we speculated that DERL1 operated as a tumor promotor in HCC, and its expression might be proposed as a predictor for tumor metastasis of human HCC. Interference of DERL1 markedly blocked cell proliferation and migration, and induced the apoptosis of HCC cells in vitro. Phosphorylation of Akt was significantly inhibited in cells transfected with DERL1 siRNA compared to their control cells in HuH7 and Hep3B cell lines. The opposite result was observed in the DERL1 overexpression cells. Conclusion:Our findings prove that DERL1 promotes tumor progression via AKT pathway and provide a new potential target for the clinical treatment and diagnosis of human HCC.

SUBMITTER: Fan J

PROVIDER: S-EPMC7295458 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Derlin-1 Promotes the Progression of Human Hepatocellular Carcinoma via the Activation of AKT Pathway.

Fan Jiye J Tian Liying L Huang Shuhong S Zhang Jing J Zhao Baohua B

OncoTargets and therapy 20200611

<h4>Introduction</h4>Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. In the present research, we explored a new oncogene, derlin-1 (DERL1), and studied its role and mechanism in human HCC.<h4>Methods</h4>We assessed the expression and prognosis value of DERL1 in human HCC by using GEPIA dataset analysis and immunohistochemistry. To elucidate the specific function of DERL1, we suppressed its expression in two HCC cell lines, HuH7 and Hep3B, and overexpressed D ...[more]

PMID: 32606758

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Project description:BackgroundHepatocellular carcinoma (HCC) is the fourth fatal malignant tumour type worldwide. However, the exact molecular mechanism involved in HCC progression remains unclear.MethodsThree pairs of HCC and matched portal vein tumour thrombus (PVTT) tissue samples were analysed by isobaric tags for relative and absolute quantification (iTRAQ) assay to investigate the differentially expressed proteins. Real-time quantitative PCR, immunostaining, and immunoblotting were performed to detect cofilin 1 (CFL1) in HCC and non-tumour tissues. CCK8 and EdU, and Transwell assays, respectively, determined cell proliferation, migration, and invasion of HCC cells. Further, subcutaneous and tail vein injection were performed in nude mice for investigating HCC growth and lung metastasis in vivo. Regulatory effect of hypoxia-inducible factor-1α (HIF-1α) on CFL1 was confirmed by chromatin immunoprecipitation (ChIP) assay. Finally, interaction between CFL1 and phospholipase D1 (PLD1) was studied using immunoprecipitation (IP) assay.ResultsThe iTRAQ analysis identified expression of CFL1 to be significantly upregulated in PVTT than in HCC tissues. Increased expression of CFL1 was closely associated with unfavourable clinical features, and was an independent risk predictor of overall survival in HCC patients. The knockdown of CFL1 inhibited cell growth viability, invasiveness, and epithelial-mesenchymal transformation (EMT) in HCC cells. Furthermore, CFL1 silencing significantly suppressed the growth and lung metastasis of HCC cells in nude mice. Next, HIF-1α directly regulated CFL1 transcription by binding to the hypoxia-responsive element (HRE) in the promoter. Moreover, we disclosed the interaction between CFL1 and PLD1 in HCC cells using IP assay. Mechanistically, CFL1 maintained PLD1 expression by repressing ubiquitin-mediated protein degradation, thereby activating AKT signalling in HCC cells. Notably, the CFL1/PLD1 axis was found mediating the hypoxia-induced activation of the AKT pathway and EMT.ConclusionThe analysis suggests that hypoxia-induced CFL1 increases the proliferation, migration, invasion, and EMT in HCC by activating the PLD1/AKT pathway.

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Derlin-1 Promotes the Progression of Human Hepatocellular Carcinoma via the Activation of AKT Pathway.

Publications

Derlin-1 Promotes the Progression of Human Hepatocellular Carcinoma via the Activation of AKT Pathway.

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