Signal transducer and activator of transcription 3 promotes the Warburg effect possibly by inducing pyruvate kinase M2 phosphorylation in liver precancerous lesions

• Published in: World journal of gastroenterology : WJG 2019-04, Vol.25 (16), p.1936-1949
• Main Authors: Bi, Yang-Hui, Han, Wen-Qi, Li, Ruo-Fei, Wang, Yun-Jiao, Du, Zun-Shu, Wang, Xue-Jiang, Jiang, Ying
• Format: Article
• Language: English
• Subjects: Animals; Basic Study; Cell Line; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - pathology; Cyclic S-Oxides - pharmacology; Disease Models, Animal; Glycolysis - drug effects; Hepatocytes; Humans; Hydrogen Peroxide - toxicity; Liver - cytology; Liver - pathology; Liver Neoplasms - pathology; Male; Methylnitronitrosoguanidine - toxicity; Phosphorylation - drug effects; Precancerous Conditions - chemically induced; Precancerous Conditions - pathology; Pyruvate Kinase - metabolism; Rats; Rats, Wistar; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Stem Cells; Up-Regulation
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v25.i16.1936

Study shows that signal transducer and activator of transcription 3 (STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 in myeloma. STAT3 and pyruvate kinase M2 (PKM2) can also be activated and enhance the Warburg effect in hepatocellular carcinoma. Precancerous lesions are critical to human and rodent hepatocarcinogenesis. However, the underlying molecular mechanism for the development of liver precancerous lesions remains unknown. We hypothesized that STAT3 promotes the Warburg effect possibly by upregulating p-PKM2 in liver precancerous lesions in rats. To investigate the mechanism of the Warburg effect in liver precancerous lesions in rats. A model of liver precancerous lesions was established by a modified Solt-Farber method. The liver pathological changes were observed by HE staining and immunohistochemistry. The transformation of WB-F344 cells induced with N-methyl-N'-nitro-N-nitrosoguanidine and hydrogen peroxide was evaluated by the soft agar assay and aneuploidy. The levels of glucose and lactate in the tissue and culture medium were detected with a spectrophotometer. The protein levels of glutathione S-transferase-π, proliferating cell nuclear antigen (PCNA), STAT3, and PKM2 were examined by Western blot and immunofluorescence. We found that the Warburg effect was increased in liver precancerous lesions in rats. PKM2 and p-STAT3 were upregulated in activated oval cells in liver precancerous lesions in rats. The Warburg effect, p-PKM2, and p-STAT3 expression were also increased in transformed WB-F344 cells. STAT3 activation promoted the clonal formation rate, aneuploidy, alpha-fetoprotein expression, PCNA expression, G1/S phase transition, the Warburg effect, PKM2 phosphorylation, and nuclear translocation in transformed WB-F344 cells. Moreover, the Warburg effect was inhibited by stattic, a specific inhibitor of STAT3, and further reduced in transformed WB-F344 cells after the intervention for PKM2. The Warburg effect is initiated in liver precancerous lesions in rats. STAT3 activation promotes the Warburg effect by enhancing the phosphorylation of PKM2 in transformed WB-F344 cells.