Abstract
SLC5A8 has been shown to be associated with a large number of cancer progressions. However, the biological functions of SLC5A8 in hepatocellular carcinoma (HCC) remain largely unclear. Therefore, we performed this research to explore the functions of SLC5A8 in HCC progression. In this study, SLC5A8 protein and mRNA expression were examined by immunohistochemistry and quantitative real-time PCR, respectively, and we found significantly lower expression levels in HCCs than in the corresponding normal liver tissues. Low SLC5A8 expression was significantly correlated with the clinicopathological features of HCC patients. Patients with low SLC5A8 expression have a shorter overall survival time. This interpretation is confirmed by the results obtained from our in vitro experiments; functional assays indicated that overexpression of SLC5A8, by infection with a recombinant plasmid containing SLC5A8, significantly suppressed HCC cell growth, invasion, and migration and induced HCC cell apoptosis. Moreover, the expression levels of beta-catenin, cyclin D1, c-Myc, MMP-2, and FAK detected by western blotting were downregulated in SLC5A8-transfected HCC cells compared with control-transfected cells, indicating that SLC5A8 has a tumor-suppressive function that acts by interfering with Wnt/β-catenin signaling in HCC.
Similar content being viewed by others
References
Schütte K, Bornschein J, Malfertheiner P. Hepatocellular carcinoma--epidemiological trends and risk factors. Dig Dis. 2009;27:80–92. doi:10.1159/000218339.
Fernandez-Banet J, Lee NP, Chan KT, Gao H, Liu X, Sung W-K, et al. Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma. Genomics. 2014;103:189–203. doi:10.1016/j.ygeno.2014.01.003.
Wu JN, Roberts CW. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 2013;3:35–43. doi:10.1158/2159-8290.CD-12-0361.
Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63. doi:10.1002/hep.22580.
Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87. doi:10.1038/nrc1934.
Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27. doi:10.1002/hep.22506.
Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB, et al. Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res. 2007;24:575–84. doi:10.1007/s11095-006-9176-1.
Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, et al. Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J Neurochem. 2006;98:279–88. doi:10.1111/j.1471-4159.2006.03878.x.
Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 2006;78:2419–25. doi:10.1016/j.lfs.2005.10.028.
Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, et al. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res. 2006;66:11560–4. doi:10.1158/0008-5472.CAN-06-1950.
Park JY, Kim D, Yang M, Park HY, Lee SH, Rincon M, et al. Gene silencing of SLC5A8 identified by genome-wide methylation profiling in lung cancer. Lung Cancer. 2013;79:198–204. doi:10.1016/j.lungcan.2012.11.019.
Dong SM, Lee EJ, Jeon ES, et al. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol. 2005;18:170–8. doi:10.1038/modpathol.3800261.
Ganapathy V, Gopal E, Miyauchi S, Prasad PD. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem Soc Trans. 2005;33:237–40. doi:10.1042/BST0330237.
Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, et al. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res. 2005;65:3617–23. doi:10.1158/0008-5472.CAN-05-0048.
Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, et al. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab. 2005;90:3028–35. doi:10.1210/jc.2004-1394.
Ueno M, Toyota M, Akino K, Suzuki H, Kusano M, Satoh A, et al. Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol. 2004;25:134–40. doi:10.1159/000079145.
Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, et al. Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor. Cancer Detect Prev. 2007;31:359–65. doi:10.1016/j.cdp.2007.09.002.
Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, et al. Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas. 2008;36:e32–9.
Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003;100:8412–7. doi:10.1073/pnas.1430846100.
Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S, Mariadason JM, et al. Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A. 2006;103:7270–5. doi:10.1073/pnas.0602365103.
Whitman SP, Hackanson B, Liyanarachchi S, Liu S, Rush LJ, Maharry K, et al. DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication. Blood. 2008;112:2013–6. doi:10.1182/blood-2008-01-128595.
Liu WB, Liu JY, Ao L, Zhou ZY, Zhou YH, Cui ZH, et al. Epigenetic silencing of cell cycle regulatory genes during 3-methylcholanthrene and diethylnitrosamine-induced multistep rat lung cancer. Mol Carcinog. 2010;49:556–65. doi:10.1002/mc.20621.
Xu J, HY X, Zhang Q, Song F, Jiang JL, Yang XM, et al. HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. Mol Cancer Res. 2007;5:605–14. doi:10.1158/1541-7786.MCR-06-0286.
Acknowledgments
This project was supported by the Jiangsu Provincial Natural Science Foundation of China (Grant No. BK20131095).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflicts of interest
None.
Additional information
Ben-Shun Hu and Shu-Ming Xiong contributed to this paper equally.
Rights and permissions
About this article
Cite this article
Hu, BS., Xiong, SM., Li, G. et al. Downregulation of SLC5A8 inhibits hepatocellular carcinoma progression through regulation of Wnt/β-catenin signaling. Tumor Biol. 37, 13445–13453 (2016). https://doi.org/10.1007/s13277-016-5170-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5170-3