Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that several microRNAs (miRNAs) are involved in hepatocellular carcinoma (HCC) tumorigenesis and metastasis; however, the mechanisms responsible for the differences in the functions of these miRNAs in liver cancer remain a mystery. In our previous study, we identified NUDT21 as an interaction partner of argonaute 2 (AGO2). NUDT21 has been reported to be involved in alternative polyadenylation (APA); thus, the interaction between NUDT21 and AGO2 may be a key component of the crosstalk between APA and miRNA-mediated gene silencing in HCC. Our data showed that NUDT21 expression was decreased in HCC. Moreover, our results showed that NUDT21 co-localized with AGO2 in P/GW bodies in normal liver cells; however, this co-localization was diminished in cancer cells. Functional studies showed that NUDT21 elongated the 3'-UTR of mRNA and enhanced the efficiency of miRNA-mediated gene silencing by increasing the efficiency of AGO2-mRNA binding, which played an important role in cell proliferation. In summary, loss of NUDT21 shortened the 3'-UTR of various oncogenes in HCC cells. The shorter 3'-UTR contained less miRNA binding sites, which enabled the oncogenes to evade miRNA regulation and become overexpressed in HCC, leading to unregulated cancer cell proliferation.
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PMID:NUDT21 regulates 3'-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. 2896 83

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.
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PMID:NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. 2978 Jan 66

Circular RNAs (circRNAs) are a novel class of RNAs, which involve in many physiological processes and participate in many diseases, especially in cancer. Previous reports showed circRNAs were globally downregulated in hepatocellular carcinoma (HCC) and a lot of circRNAs involved in the tumorigenesis and metastasis of HCC. To understand the underlying mechanism of circRNAs' reduction, we explored the relationship between circRNA biogenesis and NUDT21, which was a RNA splice factor downregulated in HCC, and we found that NUDT21 elevated the formation of circRNA, and the UGUA sequences were critical for the cyclization of circRNA. Knockdown of NUDT21 disrupted the competitive endogenous RNA (ceRNA) pathway of circRNA-miRNA-mRNA, and overexpression of the downregulated circRNA could assist the NUDT21-mediated tumor suppression in HCC cells. In conclusion, the loss of NUDT21 prevented the cyclization of circRNA in HCC; without circRNA absorption, miRNAs were released to suppress the tumor-suppressor genes, leading to the uncontrolled cell proliferation.
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PMID:NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. 3157 Jul 91