Sensitization of hepatocellular carcinoma cells to irradiation by miR‑34a through targeting lactate dehydrogenase‑A

Li,Xiaogang; Lu,Ping; Li,Bo; Yang,Rong; Chu,Yan; Zhang,Zhiping; Wan,Hongwei; Niu,Chao; Wang,Chunxiao; Luo,Kaiyuan

doi:10.3892/mmr.2016.4974

Sensitization of hepatocellular carcinoma cells to irradiation by miR‑34a through targeting lactate dehydrogenase‑A

Authors:
- Xiaogang Li
- Ping Lu
- Bo Li
- Rong Yang
- Yan Chu
- Zhiping Zhang
- Hongwei Wan
- Chao Niu
- Chunxiao Wang
- Kaiyuan Luo
View Affiliations

Affiliations: Department of General Surgery, The Second People's Hospital of Yunnan Province, Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China, Department of Vascular Surgery, The Second People's Hospital of Yunnan Province, Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China
Published online on: March 3, 2016 https://doi.org/10.3892/mmr.2016.4974
Pages: 3661-3667

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Radiation is a therapeutic strategy for the treatment of cancer, and is also used for the treatment of hepatocellular carcinoma. MicroRNAs (miRs) are endogenous, non‑coding single‑stranded RNA molecules, which regulate gene expression at the post‑transcriptional level. In the present study, the roles of miR‑34a‑mediated glycolysis in radiation sensitivity were investigated. By establishing a radioresistant liver cancer cell line, the present study compared the expression level of miR‑34a from radiosensitive and radioresistant cells using the reverse transcription‑quantitative polymerase chain reaction. The glucose uptake and lactate production were also compared between the two types of cells. The results demonstrated that miR‑34a acted as a tumor suppressor in human hepatocellular cancer cells. Following comparison of radiosensitive and radioresistant cancer cells, the results of the present study demonstrated that miR‑34a was negatively correlated with radiation resistance; and levels of miR‑34a were significantly downregulated in the HepG2 radioresistant cells. Furthermore, the rate of glycolysis in the radioresistant cells was elevated, and there was evidence that glucose uptake and lactate production increased. Lactate dehydrogenase A (LDHA), which is a key enzyme in the glycolysis signaling pathway, was found to be a target of miR‑34a in hepatocellular cancer cells. Notably, the overexpression of miR‑34a re‑sensitized HepG2 radioresistant cells to radiation treatment by inhibiting LDHA. The results of the present study revealed a negative correlation between miR‑34a and glycolysis, caused by the targeting of LDHA‑34a, providing a novel mechanism for miR‑34a‑mediated radioresistance.

View Figures

View References

1	Karaman B, Battal B, Sari S and Verim S: Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol. 20:18059–18060. 2014.PubMed/NCBI
2	Olsen SK, Brown RS and Siegel AB: Hepatocellular carcinoma: Review of current treatment with a focus on targeted molecular therapies. Therap Adv Gastroenterol. 3:55–66. 2010. View Article : Google Scholar : PubMed/NCBI
3	Hong TS: Radiotherapy for hepatocellular carcinoma with tumor vascular thrombus: Ready for prime time? J Clin Oncol. 31:1619–1620. 2013. View Article : Google Scholar : PubMed/NCBI
4	Singh S, Singh PP, Roberts LR and Sanchez W: Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 11:45–54. 2014. View Article : Google Scholar
5	Klein J and Dawson LA: Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. Int J Radiat Oncol Biol Phys. 87:22–32. 2013. View Article : Google Scholar
6	Ha M and Kim VN: Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 15:509–524. 2014. View Article : Google Scholar : PubMed/NCBI
7	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar : PubMed/NCBI
8	Nelson KM and Weiss GJ: MicroRNAs and cancer: Past, present and potential future. Mol Cancer Ther. 7:3655–3660. 2008. View Article : Google Scholar : PubMed/NCBI
9	Bouyssou JM, Manier S, Huynh D, Issa S, Roccaro AM and Ghobrial IM: Regulation of microRNAs in cancer metastasis. Biochim Biophys Acta. 1845:255–265. 2014.PubMed/NCBI
10	Dumortier O, Hinault C and Van Obberghen E: MicroRNAs and metabolism crosstalk in energy homeostasis. Cell Metab. 18:312–324. 2013. View Article : Google Scholar : PubMed/NCBI
11	Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, Zarone MR, Gullà A, Tagliaferri P, Tassone P and Caraglia M: Mir-34: A new weapon against cancer? Mol Ther Nucleic Acids. 3:e1942014. View Article : Google Scholar : PubMed/NCBI
12	Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, et al: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 26:745–752. 2007. View Article : Google Scholar : PubMed/NCBI
13	Cole KA, Attiyeh EF, Mosse YP, Laquaglia MJ, Diskin SJ, Brodeur GM and Maris JM: A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res. 6:735–742. 2008. View Article : Google Scholar : PubMed/NCBI
14	Li XJ, Ren ZJ and Tang JH: MicroRNA-34a: A potential therapeutic target in human cancer. Cell Death Dis. 5:e13272014. View Article : Google Scholar : PubMed/NCBI
15	Miao P, Sheng S, Sun X, Liu J and Huang G: Lactate dehydrogenase A in cancer: A promising target for diagnosis and therapy. IUBMB Life. 65:904–910. 2013. View Article : Google Scholar : PubMed/NCBI
16	Hennessey D, Martin LM, Atzberger A, Lynch TH, Hollywood D and Marignol L: Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol Oncol. 31:1106–1116. 2013. View Article : Google Scholar
17	Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, et al: Warburg effect in chemo-sensitivity: Targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer. 9:332010. View Article : Google Scholar
18	Shimura T, Noma N, Sano Y, Ochiai Y, Oikawa T, Fukumoto M and Kunugita N: AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells. Radiother Onco. 112:302–307. 2014. View Article : Google Scholar
19	Li XJ, Ji MH, Zhong SL, Zha QB, Xu JJ, Zhao JH and Tang JH: MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. Arch Med Res. 43:514–521. 2012. View Article : Google Scholar : PubMed/NCBI
20	Akao Y, Noguchi S, Iio A, Kojima K, Takagi T and Naoe T: Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett. 300:197–204. 2011. View Article : Google Scholar
21	Zhao J, Kelnar K and Bader AG: In-depth analysis shows synergy between erlotinib and miR-34a. PLoS One. 9:e891052014. View Article : Google Scholar : PubMed/NCBI
22	Kojima K, Fujita Y, Nozawa Y, Deguchi T and Ito M: MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate. 70:1501–1512. 2010. View Article : Google Scholar : PubMed/NCBI
23	Martinez-Outschoorn UE, Lin Z, Ko YH, Goldberg AF, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F and Lisanti MP: Understanding the metabolic basis of drug resistance: Therapeutic induction of the warburg effect kills cancer cells. Cell Cycle. 10:2521–2528. 2011. View Article : Google Scholar : PubMed/NCBI
24	Zhao Y, Liu H, Liu Z, Ding Y, Ledoux SP, Wilson GL, Voellmy R, Lin Y, Lin W, Nahta R, et al: Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Res. 71:4585–4597. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zhong J, Rajaram N, Brizel DM, Frees AE, Ramanujam N, Batinic-Haberle I and Dewhirst MW: Radiation induces aerobic glycolysis through reactive oxygen species. Radiother Oncol. 106:390–396. 2013. View Article : Google Scholar : PubMed/NCBI
26	Baskar R, Lee KA, Yeo R and Yeoh KW: Cancer and radiation therapy: Current advances and future directions. Int J Med Sci. 9:193–199. 2012. View Article : Google Scholar : PubMed/NCBI
27	Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL and Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 107:2037–2042. 2010. View Article : Google Scholar : PubMed/NCBI