The Expression and Correlation of PKM2 and YAP in Hepatocellular Carcinoma Tissue_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 ZHANGXiao-dong , YANGZhao-guo , YANGLiang , MAYing-bo ,  LIHang-yu

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China;

Corresponding author：

LIHang-yu, Email: li_hangyu@126.com

Keywords：

Pyruvate kinase M2; Yes association protein; Hepatocellular carcinoma; Adjacent tissue

DOI：

10.7507/1007-9424.20160367

Video：

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Objective To investigate the significance of expression and correlation of pyruvate kinase M2 (PKM2) and yes association protein (YAP) in hepatocellular carcinoma (HCC) tissue, and then explore the relationship between the 2 kinds of protein. Methods A total of 120 patients' HCC tissues and adjacent tissues were collected retrospectively, who treated in our hospital from Apr. 2010 to Oct. 2013, the expressions of PKM2 and YAP protein in these HCC tissues and adjacent tissues were detected by SP immunohistochemical method, and then analyzed the relationship between the expressions of PKM2 and YAP ptotein with the clinicopathological features of HCC. Of the 120 patients, the expressions of YAP and PKM2 protein and its mRNA in 50 cases of HCC tissues and adjacent tissues were also examined by Western blot and real-time PCR methods respectively. Results ① The immunohistochemical results showed that, the positive rate of PKM2 protein and YAP protein in HCC tissues were 67.50% (81/120) and 71.67% (86/120) respectively, which were both higher than those of adjacent tissues[PKM2 protein:20.83% (25/120); YAP protein:29.17% (35/120)], P < 0.050. ② The expression of PKM2 protein was significantly positively correlated with the expression of YAP protein in HCC tissues (r=0.519, P < 0.001). ③ In HCC tissues, the expression of PKM2 protein was significantly correlated with the diameter of tumor, TNM staging, differentiation of HCC, and lever of alpha fetal protein (P < 0.050), and the expression of YAP protein was significantly correlated with the differentiation of HCC and lever of alpha fetal protein (P < 0.050). ④ Western blot results showed that, the expression levels of PKM2 protein and YAP protein in HCC tissues were 1.25± 0.11 and 1.08±0.10 respectively, which were significantly higher than those of adjacent tissues (PKM2 protein:0.38±0.01, YAP protein:0.41±0.02), P < 0.050. ⑤ Real-time PCR assays results showed that, basing the expressions of PKM2 mRNA and YAP mRNA in adjacent tissues (both as 1), expressions of PKM2 mRNA and YAP mRNA in HCC tissues were 11.38±0.35 and 19.96±0.48 respectively, which were both higher than those of adjacent tissues (P < 0.050). Conclusion PKM2 and YAP protein were related to the initiation of HCC, and they were also closely correlated with the differentiation and prognosis of HCC.

Citation： ZHANGXiao-dong, YANGZhao-guo, YANGLiang, MAYing-bo, LIHang-yu. The Expression and Correlation of PKM2 and YAP in Hepatocellular Carcinoma Tissue. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2016, 23(12): 1443-1449. doi: 10.7507/1007-9424.20160367 Copy

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2.	许磊波, 王捷, 刘超.不同分期系统对晚期肝癌肝切除患者生存的预测价值比较.中国普外基础与临床杂志, 2014, 21(2):138-141.
3.	Moreno-Sánchez R, Marín-Hernández A, Saavedra E, et al. Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol, 2014, 50:10-23.
4.	Kamphorst JJ, Gottlieb E. Cancer metabolism:friendly neighbours feed tumour cells. Nature, 2016, 536(7617):401-402.
5.	Hu H, Juvekar A, Lyssiotis CA, et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell, 2016, 164(3):433-446.
6.	Wong N, Ojo D, Yan J, et al. PKM2 contributes to cancer metabolism. Cancer Lett, 2015, 356(2 Pt A):184-191.
7.	Liu VM, Vander Heiden MG. The role of pyruvate kinase M2 in cancer metabolism. Brain Pathol, 2015, 25(6):781-783.
8.	敬怀志, 邱峰, 陈世知, 等.非小细胞肺癌中TRIM25和PKM2蛋白表达.南方医科大学学报, 2015, 35(3):437-441.
9.	Hjerpe E, Egyhazi Brage S, Carlson J, et al. Metabolic markers GAPDH, PKM2, ATP5B and BEC-index in advanced serous ovarian cancer. BMC Clin Pathol, 2013, 13(1):30-38.
10.	Steinhardt AA, Gayyed MF, Klein AP, et al. Expression of yes-associated protein in common solid tumors. Hum Pathol, 2008, 39(11):1582-1589.
11.	Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 2015, 163(4):811-828.
12.	Santinon G, Pocaterra A, Dupont S. Control of YAP/TAZ activity by metabolic and nutrient-sensing pathways. Trends Cell Biol, 2016, 26(4):289-299.
13.	Sobin LH, Compton CC. TNM seventh edition:what's new, what's changed communication from the international union against cancer and the American joint committee on cancer. Cancer, 2010, 116(22):5336-5339.
14.	Li Y, Zhai Z, Liu D, et al. CD105 promotes hepatocarcinoma cell invasion and metastasis through VEGF. Tumour Biol, 2015, 36(2):737-745.
15.	Li H, Sui C, Kong F, et al. Expression of HSP70 and JNK-related proteins in human liver cancer:potential effects on clinical outcome. Dig Liver Dis, 2007, 39(7):663-670.
16.	Kee HJ, Cheong JH. Tumor bioenergetics:an emerging avenue for cancer metabolism targeted therapy. BMB Rep, 2014, 47(3):158-166.
17.	Guarente L. The many faces of sirtuins:Sirtuins and the Warburg effect. Nat Med, 2014, 20(1):24-25.
18.	Hitosugi T, Kang S, Vander Heiden MG, et al. Tyrosine phosphory-lation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal, 2009, 2(97):ra73.
19.	Azoitei N, Becher A, Steinestel K, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1 alpha through NF-kappa B activation. Mol Cancer, 2016, 15(1):3-18.
20.	Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One, 2012, 7(5):e36764.
21.	Sun Q, Chen X, Ma J, et al. Mammalian target of rapamycin upregulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci U S A, 2011, 108(10):4129-4134.
22.	Xu MZ, Yao TJ, Lee NP, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer, 2009, 115(19):4576-4585.
23.	Liu JY, Li YH, Lin HX, et al. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer, 2013, 13(1):349-356.
24.	Nguyen LT, Tretiakova MS, Silvis MR, et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell, 2015, 27(6):797-808.
25.	DeRan M, Yang J, Shen CH, et al. Energy stress regulates Hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep, 2014, 9(2):495-503.
26.	Wang W, Xiao ZD, Li X, et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol, 2015, 17(4):490-499.
27.	Enzo E, Santinon G, Pocaterra A, et al. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J, 2015, 34(10):1349-1370.

1. Yang G, Wang Y, Zeng Y, et al. Rapid health transition in China, 1990-2010:findings from the Global Burden of Disease Study 2010. Lancet, 2013, 381(9882):1987-2015.
2. 许磊波, 王捷, 刘超.不同分期系统对晚期肝癌肝切除患者生存的预测价值比较.中国普外基础与临床杂志, 2014, 21(2):138-141.
3. Moreno-Sánchez R, Marín-Hernández A, Saavedra E, et al. Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol, 2014, 50:10-23.
4. Kamphorst JJ, Gottlieb E. Cancer metabolism:friendly neighbours feed tumour cells. Nature, 2016, 536(7617):401-402.
5. Hu H, Juvekar A, Lyssiotis CA, et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell, 2016, 164(3):433-446.
6. Wong N, Ojo D, Yan J, et al. PKM2 contributes to cancer metabolism. Cancer Lett, 2015, 356(2 Pt A):184-191.
7. Liu VM, Vander Heiden MG. The role of pyruvate kinase M2 in cancer metabolism. Brain Pathol, 2015, 25(6):781-783.
8. 敬怀志, 邱峰, 陈世知, 等.非小细胞肺癌中TRIM25和PKM2蛋白表达.南方医科大学学报, 2015, 35(3):437-441.
9. Hjerpe E, Egyhazi Brage S, Carlson J, et al. Metabolic markers GAPDH, PKM2, ATP5B and BEC-index in advanced serous ovarian cancer. BMC Clin Pathol, 2013, 13(1):30-38.
10. Steinhardt AA, Gayyed MF, Klein AP, et al. Expression of yes-associated protein in common solid tumors. Hum Pathol, 2008, 39(11):1582-1589.
11. Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 2015, 163(4):811-828.
12. Santinon G, Pocaterra A, Dupont S. Control of YAP/TAZ activity by metabolic and nutrient-sensing pathways. Trends Cell Biol, 2016, 26(4):289-299.
13. Sobin LH, Compton CC. TNM seventh edition:what's new, what's changed communication from the international union against cancer and the American joint committee on cancer. Cancer, 2010, 116(22):5336-5339.
14. Li Y, Zhai Z, Liu D, et al. CD105 promotes hepatocarcinoma cell invasion and metastasis through VEGF. Tumour Biol, 2015, 36(2):737-745.
15. Li H, Sui C, Kong F, et al. Expression of HSP70 and JNK-related proteins in human liver cancer:potential effects on clinical outcome. Dig Liver Dis, 2007, 39(7):663-670.
16. Kee HJ, Cheong JH. Tumor bioenergetics:an emerging avenue for cancer metabolism targeted therapy. BMB Rep, 2014, 47(3):158-166.
17. Guarente L. The many faces of sirtuins:Sirtuins and the Warburg effect. Nat Med, 2014, 20(1):24-25.
18. Hitosugi T, Kang S, Vander Heiden MG, et al. Tyrosine phosphory-lation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal, 2009, 2(97):ra73.
19. Azoitei N, Becher A, Steinestel K, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1 alpha through NF-kappa B activation. Mol Cancer, 2016, 15(1):3-18.
20. Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One, 2012, 7(5):e36764.
21. Sun Q, Chen X, Ma J, et al. Mammalian target of rapamycin upregulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci U S A, 2011, 108(10):4129-4134.
22. Xu MZ, Yao TJ, Lee NP, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer, 2009, 115(19):4576-4585.
23. Liu JY, Li YH, Lin HX, et al. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer, 2013, 13(1):349-356.
24. Nguyen LT, Tretiakova MS, Silvis MR, et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell, 2015, 27(6):797-808.
25. DeRan M, Yang J, Shen CH, et al. Energy stress regulates Hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep, 2014, 9(2):495-503.
26. Wang W, Xiao ZD, Li X, et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol, 2015, 17(4):490-499.
27. Enzo E, Santinon G, Pocaterra A, et al. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J, 2015, 34(10):1349-1370.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The Expression and Correlation of PKM2 and YAP in Hepatocellular Carcinoma Tissue

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