The clinical and pathological significance of mitochondrial pyruvate carriers in hepatocellular carcinoma

Abstract

Abstract: Objective Mitochondrial pyruvate carrier (MPC) plays an important pathophysiological role in the metabolism of tumor cells. However, there are few studies about the effects of MPC in the development of malignant tumors, especially hepatocellular carcinoma (HCC). The aim of this study was to analyze the correlation between the expression of MPC in HCC and the levels of clinicopathological parameters, and to evaluate the predictive value of MPC for recurrence and prognosis of HCC after operation.Methods MPC1 and MPC2 protein expression levels in 85 cases of carcinoma and adjacent tissue specimens were detected by immunohistochemistry. The relative expression levels of MPC1 and MPC2 were calculated by Image-Pro Plus software. The correlation between the protein expressions of MPC1 and MPC2 and the levels of clinical pathological parameters was analyzed between patients grouped according to the relative expressions of MPC1 and MPC2. Kaplain-Meier survival analysis was used to analyze the correlation between the protein expression of MPC and the recurrence, prognosis of patients with HCC. Cox regression models were established to determine independent risk factors for recurrence of HCC after operation.Results In paraffin-embedded specimens, the protein expressions of MPC1 and MPC2 in tumor tissues were significantly lower than those in adjacent tissues. There was no significant correlation between MPC1, MPC2 levels and clinical pathological parameters (P>0.05). In patients with lower expression of MPC1, the recurrence rate (P=0.000) was higher and the overall survival time (P=0.001) was shorter. However, the expression level of MPC2 was not correlated with recurrence rate (P=0.254) or overall survival (P=0.452). The decreased expression of MPC1 protein (P=0.000) and microvascular invasion (P=0.017) were independent risk factors for postoperative recurrence of HCC. Univariate and multivariate analyses showed that MPC2 was not associated with postoperative recurrence (P=0.230).Conclusion The absence or reduced activity of MPC1 and MPC2 protein in HCC is widespread. And the expression of MPC1 protein is associated with postoperative recurrence and prognosis of HCC, which can be used as a new biomarkers for clinical prognosis prediction and risk stratification in postoperative patients with HCC.

Key words: Hepatocellular carcinoma, Mitochondrial pyruvate carrier, Survival analysis, Prognosis, Energy metabolism

MA Xiang-ming, HOU Jing-yue, FU Qing-jiang, CAO Li-ying.. The clinical and pathological significance of mitochondrial pyruvate carriers in hepatocellular carcinoma[J]. Chinese Hepatolgy, 2020, 25(6): 573-577.

References 15

[1]	Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136: E359-86.
[2]	Brito AF, Abrantes AM., Tralhao JG, et al. Targeting hepatocellular carcinoma: what did we discover so far. Oncol Rev, 2016, 10: 302.
[3]	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66: 115-132.
[4]	Ma RH, Zhang W, Tang K, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat Commun, 2013, 4:2508.
[5]	Wang CJ, Zhou ZG, Holmqvist A, et al. Survivin expression quantified by Image Pro-Plus compared with visual assessment. Appl Immunohistochem Mol Morphol, 2009, 17: 530-535.
[6]	Danhier P, Banski P, Payen VL, et al. Cancer metabolism in space and time: beyond the warburg effect. Biochim Biophys Acta, 2017,
[7]	马向明, 曹立瀛. 恶性肿瘤线粒体丙酮酸代谢障碍研究进展. 中华肿瘤防治杂志, 2019, 26: 64-69.
[8]	Schell JC, Rutter J. The long and winding road to the mitochondrial pyruvate carrier. Cancer Metab, 2013, 1: 6.
[9]	McCommis KS, Finck BN. Mitochondrial pyruvate transport: a historical perspective and future research directions. Biochem J, 2015, 466: 443-454.
[10]	Bender T, Martinou JC. The mitochondrial pyruvate carrier in health and disease: to carry or not to carry. Biochim Biophys Acta, 2016, 1863(10): 2436-2442.
[11]	Vanderperre B, Bender T, Kunji ER, et al. Mitochondrial pyruvate import and its effects on homeostasis. Curr Opin Cell Biol, 2015, 33:35-41.
[12]	Bricker DK, Taylor EB, Schell JC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science, 2012, 337: 96-100.
[13]	Herzig S, Raemy E, Montessuit S, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science, 2012, 337: 93-96.
[14]	Schell JC, Olson KA, Jiang L, et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell, 2014, 56: 400-413.
[15]	Li X, Ji Y, Han G, et al. MPC1 and MPC2 expressions are associated with favorable clinical outcomes in prostate cancer. BMC Cancer, 2016, 16: 894.