The role of Pim-2 in apoptotic signal transduction pathway of hepatocellular carcinoma
DOI:
https://doi.org/10.18203/2349-2902.isj20171146Keywords:
Apoptosis, Hepatocellular carcinoma, Pim-2Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors. The objective was to investigate the role of serine/threonine kinase Pim-2 in apoptosis signal transduction pathway, because there is little study about its contribution to apoptosis in hepatocellular carcinoma.
Methods: The Pim-2 gene and protein expression were examined by qRT-PCR, Western blot and immunohistochemical stain in HCC tissues and normal liver tissues. The plasmid pCI-neo-Pim2 was transfected into human hepatoma cell line SMMC7721 by lipofectamine. Total RNAs were extracted from SMMC7721 cell in logarithm growth phase. The mRNA expression of Pim-2, Akt-1 (protein kinase B), 4E-BP1 (translation repressor of mammalian target of rapamycln), SOCS-1 (repressor of cytokine), Bad（Bcl-xL/Bcl-2 associated death promoter, Bim（Bc1-2 interacting mediator of cell death）and Puma (p53 upregulated modulator of apoptosis) were identified by qRT-PCR. The cell cycle of post-transfected SMMC7721 cells was assessed by flow cytometry.
Results: Pim-2 expression was enhanced in HCC. In post-transfected SMMC7721 cells, Pim-2 mRNA expression was up-regulated, level of Bad mRNA was attenuated, furthermore, the transcription level of Akt-1, SOCS-1, 4E-BP1, Bim and Puma gene wasn’t variety. Up-graulated Pim-2 can’t cause distinct change of cell cycle or apoptosis in hepatoma cell.
Conclusions: The serine/threonine kinase Pim-2 plays an import role in the development of HCC, Pim-2 dependent maintenance of cell size and survival correlated with its ability to maintain down-regulated expression of the BH3 protein Bad. Pim-2 is not a trigger in cell-autonomous survival or inhibiting apoptosis in hepatocellular carcinoma. Pim-2 is a redundancy pathway of survival signaling.
References
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115-32.
Schattenberg JM, Schuchmann M, Galle PR. Cell death and hepatocarcinogenesis: Dysregulation of apoptosis signaling pathways. J Gastroenterol Hepatol. 2011;26(1):213-9.
Rohrbeck L, Gong JN, Lee EF, Kueh AJ, Behren A, Tai L, et al. Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM. Cell Death Differ. 2016;23(12):2054-62.
Ha M, Wei L, Guan X, Li L, Liu C. p53-dependent apoptosis contributes to di-(2-ethylhexyl) phthalate-induced hepatotoxicity. Environ Pollut. 2016;208(Pt B):416-25.
Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22(4):526-39.
Meyer C, Liu Y, Kaul A, Peipe I, Dooley S. Caveolin-1 abrogates TGF-beta mediated hepatocyte apoptosis. Cell Death Dis. 2013;4:e466.
Dong Z, Qi R, Guo X, Zhao X, Li Y, Zeng Z, et al. MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation. Biochem Biophys Res Commun. 2016; 483(1):630-7.
Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M. Targeting the Pim kinases in multiple myeloma. Blood Cancer J. 2015;5:e325.
Mondello P, Cuzzocrea S, Mian M. Pim kinases in hematological malignancies: where are we now and where are we going? J Hematol Oncol. 2014;7:95.
Jinesh GG, Mokkapati S, Zhu K, Morales EE. Pim kinase isoforms: devils defending cancer cells from therapeutic and immune attacks. Apoptosis. 2016;21(11):1203-13.
Jimenez-Garcia MP, Lucena-Cacace A, Robles-Frias MJ, Narlik-Grassow M, Blanco-Aparicio C, Carnero A. The role of PIM1/PIM2 kinases in tumors of the male reproductive system. Sci Rep. 2016;6:38079.
Gong J, Wang J, Ren K, Liu C, Li B, Shi Y. Serine/threonine kinase Pim-2 promotes liver tumorigenesis induction through mediating survival and preventing apoptosis of liver cell. J Surg Res. 2009;153(1):17-22.
Ren K, Zhang W, Shi Y, Gong J. Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway. Pathol Oncol Res. 2010;16(2):229-37.
Li GQ, Wang XH, Yin J, Yu Y. Zhonghua Zhong Liu Za Zhi. Construction of PCI-neo mammalian expression vector system containing murine 4-1BBL gene and its stable expression in hepatocellular carcinoma cell line. 2003;25(4):328-31.
Narlik-Grassow M, Blanco-Aparicio C, Carnero A. The PIM family of serine/threonine kinases in cancer. Med Res Rev. 2014; 34(1): 136-59.
Adam K, Lambert M, Lestang E, Champenois G, Dusanter-Fourt I, Tamburini J, et al. Control of Pim2 kinase stability and expression in transformed human haematopoietic cells. Biosci Rep. 2015;35(6):e00274.
Garcia PD, Langowski JL, Wang Y, Chen M, Castillo J, Fanton C, et al. Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014;20(7):1834-45.
Li X, Zhang XA, Xie W, Li X, Huang S. MYC-mediated synthetic lethality for treatment of hematological malignancies. Curr Cancer Drug Targets. 2015;15(1):53-70.
