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Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis.
- Source :
-
PloS one [PLoS One] 2014 Dec 26; Vol. 9 (12), pp. e115036. Date of Electronic Publication: 2014 Dec 26 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Carrier Proteins genetics
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Glycolysis
Hep G2 Cells
Humans
Liver Neoplasms genetics
Liver Neoplasms metabolism
Liver Neoplasms, Experimental
Lung Neoplasms pathology
Male
Membrane Proteins genetics
Mice
Mice, Nude
MicroRNAs metabolism
Prognosis
Thyroid Hormones genetics
Thyroid Hormone-Binding Proteins
Carcinoma, Hepatocellular pathology
Carrier Proteins metabolism
Liver Neoplasms pathology
Lung Neoplasms secondary
Membrane Proteins metabolism
MicroRNAs genetics
Thyroid Hormones metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25541689
- Full Text :
- https://doi.org/10.1371/journal.pone.0115036