PIM1 regulates glycolysis and promotes tumor progression in hepatocellular carcinoma

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Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2) was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over-expression in human HCCs was associated with a down-regulation of a liver-specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming.published_or_final_versio

MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis

MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.published_or_final_versio

Overexpression of Enhancer of Zeste homolog 2 (EZH2) promotes HCC metastasis via epigenetic silencing of multiple anti-metastatic microRNAs

Among Top Scored PostersPosters - Session 28. Molecular pathogenesis, cell biology and translational research: no. P-001BACKGROUND: Epigenetic alterations and microRNA deregulation are common events in hepatocarcinogenesis. Analyzing the expression levels of 90 epigenetic modifiers, we found that Enhancer of Zeste homolog 2 ...link_to_OA_fulltex

SUV39H1 promotes HCC tumorigenesis and is targeted by tumor suppressive miRNA-125b

Poster Session 1 - Chromatin Regulators: abstract no. 1059Epigenetic alternation is a common dysregulated event in hepatocellular carcinoma (HCC) development. Through interrogating the expression of 90 major epigenetic regulating genes, we identified SUV39H1, the prototype histone methyltransferase as one of the most frequently up-regulated epigenetic regulators in human HCC (61%, 23/38). SUV39H1 is responsible for H3K9 trimethylation establishment and essentially involves in heterochromatin formation and transcriptional repression. We found that SUV39H1 up-regulation in human HCC was significantly associated with ...link_to_OA_fulltextThe Annual Meeting of the American Association for Cancer Research (AACR 2012), Chicago, IL., 31 March-4 April 2012

Sequential alterations of microRNA expression in hepatocellular carcinoma development and venous metastasis

Hepatocellular carcinoma (HCC) is a prevalent cancer with an extremely high mortality rate attributed to HCC metastasis, which is the major cause of tumor recurrence and organ failure. Presence of tumor thrombi in the portal veins (venous metastases) is a clinicopathological feature of metastatic HCCs. In this study, we analyzed the microRNA (miRNA) expression profiles of nontumorous livers, primary HCCs, and venous metastases in the same livers from 20 HCC patients by way of TaqMan low-density array (TLDA) and identified the precise alterations of miRNA expression from nontumorous livers to primary HCCs and venous metastases globally. By unsupervised clustering analysis, nontumorous livers were distinctly segregated from primary HCCs and venous metastases, whereas no discernible difference in the expression pattern could be found between primary HCCs and venous metastases. However, a marked global reduction of miRNA expression levels was detected in venous metastases, as compared with primary HCCs. These data suggest that miRNA deregulation is an early event in liver carcinogenesis and the later global miRNA down-regulation aggravates the preexisting miRNA deregulation to further promote HCC metastasis. CONCLUSION: Our study has enriched the current understanding of the deregulation of miRNAs in HCC progression and highlighted the sequential and distinctive alterations of miRNA expression in primary HCC and venous metastasis formation.link_to_subscribed_fulltex

MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2

MicroRNAs (miRNAs) are small, noncoding RNAs that can act as oncogenes or tumor suppressors in human cancer. Our previous study showed that miR-125b was a prognostic indicator for patients with hepatocellular carcinoma (HCC), but its functions and exact mechanisms in hepatic carcinogenesis are still unknown. Here we demonstrate that miR-125b suppressed HCC cell growth in vitro and in vivo. Moreover, miR-125b increased p21Cip1/Waf1 expression and arrested cell cycle at G 1 to S transition. In addition, miR-125b inhibited HCC cell migration and invasion. Further studies revealed that LIN28B was a downstream target of miR-125b in HCC cells as miR-125b bound directly to the 3 untranslated region of LIN28B, thus reducing both the messenger RNA and protein levels of LIN28B. Silencing of LIN28B recapitulated the effects of miR-125b overexpression, whereas enforced expression of LIN28B reversed the suppressive effects of miR-125b. Conclusion: These findings indicate that miR-125b exerts tumor-suppressive effects in hepatic carcinogenesis through the suppression of oncogene LIN28B expression and suggest a therapeutic application of miR-125b in HCC. © 2010 American Association for the Study of Liver Diseases.link_to_OA_fulltex