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Elevated expression of eukaryotic translation initiation factor 3H is associated with proliferation, invasion and tumorigenicity in human hepatocellular carcinoma.

ABSTRACT: We studied the role of eukaryotic translation initiation factor 3 subunit H (EIF3H) in hepatocellular carcinoma (HCC) progression.High EIF3H expression was observed in 50.23% patients. Upregulation of EIF3H is an independent predictor for greater rates of cancer recurrence and shorter overall survival in HCC patients. Knockdown of EIF3H expression in HCC cells promoted apoptosis, and inhibited cell growth, colony formation, migration, as well as xenograft growth. TGF-?and MAPK pathways are potentially targeted by EIF3H.EIF3H mRNA expression was measured in HCC tissue samples and paired non-tumor samples (N=60) and results were validated in another dataset of 215 HCC patients. Then EIF3H expression and clinical outcomes were correlated. Malignant phenotypes were studied after EIF3H expression was knocked down with siRNA in HCC cell lines. EIF3H targeted pathways were identified by microarray analysis.EIF3H is frequently upregulated and is an independent prognostic marker for HCC patients and EIF3H inhibition mitigates the malignant phenotype. Our data provide novel insight into the function of EIF3H in HCC progression, and suggest that EIF3H may be a potentially valuable biomarker for HCC.

SUBMITTER: Zhu Q

PROVIDER: S-EPMC5226555 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Elevated expression of eukaryotic translation initiation factor 3H is associated with proliferation, invasion and tumorigenicity in human hepatocellular carcinoma.

Zhu Qian Q Qiao Guo-Liang GL Zeng Xiao-Chuan XC Li Yun Y Yan Jian-Jun JJ Duan Rui R Du Zhi-Yong ZY

Oncotarget 20160801 31

<h4>Aim</h4>We studied the role of eukaryotic translation initiation factor 3 subunit H (EIF3H) in hepatocellular carcinoma (HCC) progression.<h4>Results</h4>High EIF3H expression was observed in 50.23% patients. Upregulation of EIF3H is an independent predictor for greater rates of cancer recurrence and shorter overall survival in HCC patients. Knockdown of EIF3H expression in HCC cells promoted apoptosis, and inhibited cell growth, colony formation, migration, as well as xenograft growth. TGF- ...[more]

PMID: 27340783

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Project description:Accumulating evidence has demonstrated that aberrant microRNA (miRNA) expression is involved in hepatocellular carcinoma (HCC) progression. Previous findings suggested that miRNA (miR)‑875‑5p participates in the development of various types of cancer. However, the expression and function of miR‑875‑5p in HCC remains largely unclear. The analysis of clinical samples in the present study demonstrated that miR‑875‑5p expression was downregulated in HCC tissues compared to adjacent non‑tumor tissues, which was associated with a large tumor size, venous infiltration, advanced tumor‑node‑metastasis stage and unfavorable overall survival. In vitro experiments revealed that ectopic expression of miR‑875‑5p suppressed, whereas inhibition of miR‑875‑5p promoted HCC cell proliferation, migration, invasion and epithelial‑to‑mesenchymal transition (EMT) progression. Overexpression of miR‑875‑5p restrained HCC tumor growth and metastasis in vivo. Mechanistically, eukaryotic translation initiation factor 3 subunit a (eIF3a) was identified as the downstream target of miR‑875‑5p in HCC. Further experiments demonstrated that the expression of eIF3a was upregulated and negatively correlated with that of miR‑875‑5p in HCC tissues. In addition, miR‑875‑5p negatively regulated the luciferase activity of wild‑type, but not mutant 3'‑untranslated region (3'UTR) of eIF3a mRNA. miR‑875‑5p suppressed eIF3a expression at the mRNA and protein level in HCC cells. Additionally, eIF3a exerted an oncogenic role, and knockdown of eIF3a inhibited the proliferation, motility and EMT of HCC cells. In addition, eIF3a overexpression abolished the inhibitory effects of miR‑875‑5p on the proliferation, motility and EMT in HCC cells. In conclusion, miR‑875‑5p, which was downregulated in HCC, may inhibit tumor growth and metastasis by eIF3a downregulation via targeting its 3'UTR and may be a promising prognostic and therapeutic strategy in HCC.

Project description:Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2‑mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription‑quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient‑derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5‑ethynyl‑2'‑deoxyuridine, lactate dehydrogenase release assay and calcein‑AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1‑dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.

Dataset Information

Elevated expression of eukaryotic translation initiation factor 3H is associated with proliferation, invasion and tumorigenicity in human hepatocellular carcinoma.

Publications

Elevated expression of eukaryotic translation initiation factor 3H is associated with proliferation, invasion and tumorigenicity in human hepatocellular carcinoma.

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