LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma

Zhao,Juping; Huang,Xin; Xu,Zhaoping; Dai,Jun; He,Hongchao; Zhu,Yu; Wang,Haofei

doi:10.3892/mmr.2017.7637

LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma

Authors:
- Juping Zhao
- Xin Huang
- Zhaoping Xu
- Jun Dai
- Hongchao He
- Yu Zhu
- Haofei Wang
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Affiliations: Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
Published online on: September 27, 2017 https://doi.org/10.3892/mmr.2017.7637
Pages: 8335-8344

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Abstract

Previous studies have indicated that high expression of lactate dehydrogenase A (LDHA) exists in many human cancers. Recently, several reports showed that silencing or inhibition of LDHA could suppress metastasis of human cancer including renal cell carcinoma (RCC). However, the mechanism remains unknown. The role of LDHA in RCC migration and invasion was investigated using immunohistochemistry, western blotting, Transwell and scratch assays, and in vivo experiment. The influence of LDHA on the Warburg effect was also investigated by LDHA activity and lactate production assay. LDHA was overexpressed in RCC tissues and predicted a worse survival following renal resection. Correlation analysis demonstrated that LDHA was negatively correlated with E‑cadherin and positively with N‑cadherin. Experimentally, both in vivo and in vitro experiments found downregulation of LDHA suppressed RCC cells migration and invasion by inhibiting EMT. In addition, results indicated LDHA could promote the Warburg effect. Further research presented that the LDHA inhibitor, oxamate, suppressed tumor metastasis by inhibiting LDHA activity and EMT. These results demonstrated that LDHA mediates tumor metastasis by promoting EMT in RCC, suggesting that LDHA could be a promising therapeutic target for RCC therapy.

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1	Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S and Kiemeney LA: The epidemiology of renal cell carcinoma. Eur Urol. 60:615–621. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
3	Kabaria R, Klaassen Z and Terris MK: Renal cell carcinoma: Links and risks. Int J Nephrol Renovasc Dis. 9:45–52. 2016.PubMed/NCBI
4	Moch H, Artibani W, Delahunt B, Ficarra V, Knuechel R, Montorsi F, Patard JJ, Stief CG, Sulser T and Wild PJ: Reassessing the current UICC/AJCC TNM staging for renal cell carcinoma. Eur Urol. 56:636–643. 2009. View Article : Google Scholar : PubMed/NCBI
5	Bilim V, Ougolkov A, Yuuki K, Naito S, Kawazoe H, Muto A, Oya M, Billadeau D, Motoyama T and Tomita Y: Glycogen synthase kinase-3: A new therapeutic target in renal cell carcinoma. Br J Cancer. 101:2005–2014. 2009. View Article : Google Scholar : PubMed/NCBI
6	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
7	Yuen CA, Asuthkar S, Guda MR, Tsung AJ and Velpula KK: Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: A new target gleaned from an old concept. CNS Oncol. 5:101–108. 2016. View Article : Google Scholar : PubMed/NCBI
8	Taniguchi K, Sakai M, Sugito N, Kumazaki M, Shinohara H, Yamada N, Nakayama T, Ueda H, Nakagawa Y, Ito Y, et al: PTBP1-associated microRNA-1 and −133b suppress the Warburg effect in colorectal tumors. Oncotarget. 7:18940–18952. 2016. View Article : Google Scholar : PubMed/NCBI
9	Soltysova A, Breza J, Takacova M, Feruszova J, Hudecova S, Novotna B, Rozborilova E, Pastorekova S, Kadasi L and Krizanova O: Deregulation of energetic metabolism in the clear cell renal cell carcinoma: A multiple pathway analysis based on microarray profiling. Int J Oncol. 47:287–295. 2015. View Article : Google Scholar : PubMed/NCBI
10	Lim HY, Yip YM, Chiong E, Tiong HY, Halliwell B, Esuvaranathan K and Wong KP: Metabolic signatures of renal cell carcinoma. Biochem Biophys Res Commun. 460:938–943. 2015. View Article : Google Scholar : PubMed/NCBI
11	Goldman RD, Kaplan NO and Hall TC: Lactic dehydrogenase in human neoplastic tissues. Cancer Res. 24:389–399. 1964.PubMed/NCBI
12	Sun X, Sun Z, Zhu Z, Guan H, Zhang J, Zhang Y, Xu H and Sun M: Clinicopathological significance and prognostic value of lactate dehydrogenase A expression in gastric cancer patients. PloS One. 9:e910682014. View Article : Google Scholar : PubMed/NCBI
13	Xian ZY, Liu JM, Chen QK, Chen HZ, Ye CJ, Xue J, Yang HQ, Li JL, Liu XF and Kuang SJ: Inhibition of LDHA suppresses tumor progression in prostate cancer. Tumour Biol. 36:8093–8100. 2015. View Article : Google Scholar : PubMed/NCBI
14	Qiu H, Jackson AL, Kilgore JE, Zhong Y, Chan LL, Gehrig PA, Zhou C and Bae-Jump VL: JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer. Oncotarget. 6:6915–6930. 2015. View Article : Google Scholar : PubMed/NCBI
15	Yao F, Zhao T, Zhong C, Zhu J and Zhao H: LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol. 34:25–31. 2013. View Article : Google Scholar : PubMed/NCBI
16	Fantin VR, St-Pierre J and Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 9:425–434. 2006. View Article : Google Scholar : PubMed/NCBI
17	Girgis H, Masui O, White NM, Scorilas A, Rotondo F, Seivwright A, Gabril M, Filter ER, Girgis AH, Bjarnason GA, et al: Lactate Dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer. 13:1012014. View Article : Google Scholar : PubMed/NCBI
18	Wang X, Xu L, Wu Q, Liu M, Tang F, Cai Y, Fan W, Huang H and Gu X: Inhibition of LDHA deliver potential anticancer performance in renal cell carcinoma. Urol Int. 2016.
19	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
20	Cao J, Wang H, Chen F, Fang J, Xu A, Xi W, Zhang S, Wu G and Wang Z: Galangin inhibits cell invasion by suppressing the epithelial-mesenchymal transition and inducing apoptosis in renal cell carcinoma. Mol Med Rep. 13:4238–4244. 2016. View Article : Google Scholar : PubMed/NCBI
21	Giannelli G, Koudelkova P, Dituri F and Mikulits W: Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol. 65:798–808. 2016. View Article : Google Scholar : PubMed/NCBI
22	Nakazawa M and Kyprianou N: Epithelial-mesenchymal-transition regulators in prostate cancer: Androgens and beyond. J Steroid Biochem Mol Biol. 166:84–90. 2017. View Article : Google Scholar : PubMed/NCBI
23	Smith BN and Bhowmick NA: Role of EMT in metastasis and therapy resistance. J Clin Med. 5:E172016. View Article : Google Scholar : PubMed/NCBI
24	Piva F, Giulietti M, Santoni M, Occhipinti G, Scarpelli M, Lopez-Beltran A, Cheng L, Principato G and Montironi R: Epithelial to mesenchymal transition in renal cell carcinoma: Implications for cancer therapy. Mol Diagn Ther. 20:111–117. 2016. View Article : Google Scholar : PubMed/NCBI
25	Jiang F, Ma S, Xue Y, Hou J and Zhang Y: LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer. Biochem Biophys Res Commun. 469:985–992. 2016. View Article : Google Scholar : PubMed/NCBI
26	Chen Y, Sun Y, Rao Q, Xu H, Li L and Chang C: Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status. Oncotarget. 6:31203–31215. 2015. View Article : Google Scholar : PubMed/NCBI
27	Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA and Thompson CB: ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 8:311–321. 2005. View Article : Google Scholar : PubMed/NCBI
28	Kaplan NO: Lactate dehydrogenase-structure and function. Brookhaven Symp Biol. 17:131–153. 1964.PubMed/NCBI
29	Weide B, Elsasser M, Buttner P, Pflugfelder A, Leiter U, Eigentler TK, Bauer J, Witte M, Meier F and Garbe C: Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer. 107:422–428. 2012. View Article : Google Scholar : PubMed/NCBI
30	Brown JE, Cook RJ, Lipton A and Coleman RE: Serum lactate dehydrogenase is prognostic for survival in patients with bone metastases from breast cancer: A retrospective analysis in bisphosphonate-treated patients. Clin Cancer Res. 18:6348–6355. 2012. View Article : Google Scholar : PubMed/NCBI
31	Girgis H, Masui O, White NM, Scorilas A, Rotondo F, Seivwright A, Gabril M, Filter ER, Girgis AH, Bjarnason GA, et al: Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer. 13:1012014. View Article : Google Scholar : PubMed/NCBI
32	Han T, Kang D, Ji D, Wang X, Zhan W, Fu M, Xin HB and Wang JB: How does cancer cell metabolism affect tumor migration and invasion? Cell Adh Migr. 7:395–403. 2013. View Article : Google Scholar : PubMed/NCBI
33	Sanders E and Diehl S: Analysis and interpretation of transcriptomic data obtained from extended Warburg effect genes in patients with clear cell renal cell carcinoma. Oncoscience. 2:151–186. 2015. View Article : Google Scholar : PubMed/NCBI
34	Garber K: Energy deregulation: Licensing tumors to grow. Science. 312:1158–1159. 2006. View Article : Google Scholar : PubMed/NCBI
35	Sanders E and Diehl S: Analysis and interpretation of transcriptomic data obtained from extended Warburg effect genes in patients with clear cell renal cell carcinoma. Oncoscience. 2:151–186. 2015. View Article : Google Scholar : PubMed/NCBI
36	Wang X, Xu L, Wu Q, Liu M, Tang F, Cai Y, Fan W, Huang H and Gu X: Inhibition of LDHA deliver potential anticancer performance in renal cell carcinoma. Urol Int. 2016.