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

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

Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer

2017-2018 > Academic research: refereed > Publication in refereed journal201810 bcrcVersion of RecordPublishe

Proteins, the chaperone function and heredity

In this paper I use a case study—the discovery of the chaperon function exerted by proteins in the various steps of the hereditary process—to re-discuss the question whether the nucleic acids are the sole repositories of relevant information as assumed in the information theory of heredity. The evidence I here present of a crucial role for molecular chaperones in the folding of nascent proteins, as well as in DNA duplication, RNA folding and gene control, suggests that the family of proteins acting as molecular chaperones provides information that is complementary to that stored in the nucleic acids, and equally important. A re-evaluation of the role of proteins in the hereditary process is in order away from the gene-centric approach of the information theory of heredity, to which neo-Darwinian evolutionists adhere