Downregulation of glucose‑6‑phosphate dehydrogenase by microRNA‑1 inhibits the growth of pituitary tumor cells

He,Chao; Yang,Jun; Ding,Jiawang; Li,Song; Wu,Hui; Xiong,Yan; Zhou,Fei; Jiang,Yurong; Teng,Lin; Yang,Jian

doi:10.3892/or.2018.6755

Downregulation of glucose‑6‑phosphate dehydrogenase by microRNA‑1 inhibits the growth of pituitary tumor cells

Authors:
- Chao He
- Jun Yang
- Jiawang Ding
- Song Li
- Hui Wu
- Yan Xiong
- Fei Zhou
- Yurong Jiang
- Lin Teng
- Jian Yang
View Affiliations

Affiliations: Institute of Cardiology, China Three Gorges University, Yichang, Hubei 443003, P.R. China
Published online on: October 1, 2018 https://doi.org/10.3892/or.2018.6755
Pages: 3533-3542

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

Pituitary tumors are generally intracranial neoplasms with high incidence and mortality rates. The investigation of novel factors involved in the tumorigenesis of pituitary tumors and the characterization of the underlying molecular mechanisms is urgently required for the diagnosis and treatment of pituitary tumors. Accumulating evidence has indicated that microRNAs (miRs) serve important roles in the initiation and progression of cancer. The present study found that miR‑1 was significantly downregulated in pituitary tumor tissues upon reverse transcription‑quantitative polymerase chain reaction analysis. Decreased expression of miR‑1 was associated with the progression and worse prognosis of patients with pituitary tumors. The MTT assay showed that overexpression of miR‑1 significantly suppressed proliferation. Highly expressed miR‑1 promoted the apoptosis of pituitary tumor cells upon fluorescence‑activated cell sorting analysis. Further molecular study revealed that glucose‑6‑phosphate dehydrogenase (G6PD), the first and rate‑limiting enzyme of the pentose phosphate pathway (PPP), was one of the targets of miR‑1. Western blot assays showed that overexpression of miR‑1 significantly decreased the protein level of G6PD in pituitary tumor cells without changing the mRNA level of G6PD. Consequently, oxidative PPP flux analysis revealed that suppression of G6PD by miR‑1 decreased the production of nicotinamide adenine dinucleotide phosphate and the glycolysis of pituitary cancer cells. Restoration of the expression of G6PD significantly reversed the inhibitory effect of miR‑1 on the PPP and the growth of pituitary tumor cells. Collectively, the present results uncovered the critical involvement of miR‑1 in pituitary tumors, indicating that miR‑1 is a potential therapeutic target for the treatment of pituitary tumors.

View Figures

View References

1	Laws ER: Pituitary tumor apoplexy: A review. J Intensive Care Med. 23:146–147. 2008. View Article : Google Scholar : PubMed/NCBI
2	Nasi D, Perano D, Ghadirpour R, Iaccarino C, Servadei F and Romano A: Primary pituitary neuroendocrine tumor: Case report and literature review. Surg Neurol Int. 8:1012017. View Article : Google Scholar : PubMed/NCBI
3	Ezzat S and Asa SL: Mechanisms of disease: The pathogenesis of pituitary tumors. Nat Clin Pract Endocrinol Metab. 2:220–230. 2006. View Article : Google Scholar : PubMed/NCBI
4	Jiang X and Zhang X: The molecular pathogenesis of pituitary adenomas: An update. Endocrinol Metab. 28:245–254. 2013. View Article : Google Scholar
5	Fabian MR, Sonenberg N and Filipowicz W: Regulation of mRNA translation and stability by microRNAs. Ann Rev Biochem. 79:351–379. 2010. View Article : Google Scholar : PubMed/NCBI
6	Mohr AM and Mott JL: Overview of microRNA biology. Semin Liver Dis. 35:3–11. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
8	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
9	Stilling G, Sun Z, Zhang S, Jin L, Righi A, Kovācs G, Korbonits M, Scheithauer BW, Kovacs K and Lloyd RV: MicroRNA expression in ACTH-producing pituitary tumors: Up-regulation of microRNA-122 and −493 in pituitary carcinomas. Endocrine. 38:67–75. 2010. View Article : Google Scholar : PubMed/NCBI
10	Kwak PB, Iwasaki S and Tomari Y: The microRNA pathway and cancer. Cancer Sci. 101:2309–2315. 2010. View Article : Google Scholar : PubMed/NCBI
11	Farazi TA, Spitzer JI, Morozov P and Tuschl T: miRNAs in human cancer. J Pathol. 223:102–115. 2011. View Article : Google Scholar : PubMed/NCBI
12	Qu H, Xu W, Huang Y and Yang S: Circulating miRNAs: Promising biomarkers of human cancer. Asian Pac J Cancer Prev. 12:1117–1125. 2011.PubMed/NCBI
13	Sapochnik M, Nieto LE, Fuertes M and Arzt E: Molecular mechanisms underlying pituitary pathogenesis. Biochem Genet. 54:107–119. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wang DS, Zhang HQ, Zhang B, Yuan ZB, Yu ZK, Yang T, Zhang SQ, Liu Y and Jia XX: miR-133 inhibits pituitary tumor cell migration and invasion via down-regulating FOXC1 expression. Genet Mol Res. 15:2016.
15	Yu C, Li J, Sun F, Cui J, Fang H and Sui G: Expression and clinical significance of miR-26a and pleomorphic adenoma gene 1 (PLAG1) in invasive pituitary adenoma. Med Sci Monit. 22:5101–5108. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zhou K, Zhang T, Fan Y, Serick, Du G, Wu P and Geng D: MicroRNA-106b promotes pituitary tumor cell proliferation and invasion through PI3K/AKT signaling pathway by targeting PTEN. Tumour Biol. 37:13469–13477. 2016. View Article : Google Scholar : PubMed/NCBI
17	Zheng Z, Zhang Y, Zhang Z, Yang Y and Song T: Effect of miR-106b on invasiveness of pituitary adenoma via PTEN-PI3K/AKT. Med Sci Monit. 23:1277–1285. 2017. View Article : Google Scholar : PubMed/NCBI
18	Wilfred BR, Wang WX and Nelson PT: Energizing miRNA research: A review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol Genet Metab. 91:209–217. 2007. View Article : Google Scholar : PubMed/NCBI
19	Alamoudi AA, Alnoury A and Gad H: miRNA in tumour metabolism and why could it be the preferred pathway for energy reprograming. Brief Funct Genomics. 17:157–169. 2018. View Article : Google Scholar : PubMed/NCBI
20	Antoniali G, Serra F, Lirussi L, Tanaka M, D'Ambrosio C, Zhang S, Radovic S, Dalla E, Ciani Y, Scaloni A, et al: Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nat Commun. 8:7972017. View Article : Google Scholar : PubMed/NCBI
21	Jordan SD, Krüger M, Willmes DM, Redemann N, Wunderlich FT, Brönneke HS, Merkwirth C, Kashkar H, Olkkonen VM, Böttger T, et al: Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol. 13:434–446. 2011. View Article : Google Scholar : PubMed/NCBI
22	Lynn FC: Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab. 20:452–459. 2009. View Article : Google Scholar : PubMed/NCBI
23	Ono K: MicroRNA links obesity and impaired glucose metabolism. Cell Res. 21:864–866. 2011. View Article : Google Scholar : PubMed/NCBI
24	Wamelink MM, Struys EA and Jakobs C: The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: A review. J Inherit Metab Dis. 31:703–717. 2008. View Article : Google Scholar : PubMed/NCBI
25	Jiang P, Du W and Wu M: Regulation of the pentose phosphate pathway in cancer. Protein Cell. 5:592–602. 2014. View Article : Google Scholar : PubMed/NCBI
26	Patra KC and Hay N: The pentose phosphate pathway and cancer. Trends Biochem Sci. 39:347–354. 2014. View Article : Google Scholar : PubMed/NCBI
27	Cho ES, Cha YH, Kim HS, Kim NH and Yook JI: The pentose phosphate pathway as a potential target for cancer therapy. Biomol Ther. 26:29–38. 2018. View Article : Google Scholar
28	Zheng J: Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol Lett. 4:1151–1157. 2012. View Article : Google Scholar : PubMed/NCBI
29	Akram M: Mini-review on glycolysis and cancer. J Cancer Educ. 28:454–457. 2013. View Article : Google Scholar : PubMed/NCBI
30	Li XB, Gu JD and Zhou QH: Review of aerobic glycolysis and its key enzymes-new targets for lung cancer therapy. Thorac Cancer. 6:17–24. 2015. View Article : Google Scholar : PubMed/NCBI
31	Zhang C, Zhang Z, Zhu Y and Qin S: Glucose-6-phosphate dehydrogenase: A biomarker and potential therapeutic target for cancer. Anticancer Agents Med Chem. 14:280–289. 2014. View Article : Google Scholar : PubMed/NCBI
32	Naik SN and Anderson DE: The association between glucose-6-phosphate dehydrogenase deficiency and cancer in American Negroes. Oncology. 25:356–364. 1971. View Article : Google Scholar : PubMed/NCBI
33	Messeri G, Tozzi P, Boddi V and Ciatto S: Glucose-6-phosphate dehydrogenase activity and estrogen receptors in human breast cancer. J Steroid Biochem. 19:1647–1650. 1983. View Article : Google Scholar : PubMed/NCBI
34	Pisano M, Cocco P, Cherchi R, Onnis R and Cherchi P: Glucose-6-phosphate dehydrogenase deficiency and lung cancer: A hospital based case-control study. Tumori. 77:12–15. 1991. View Article : Google Scholar : PubMed/NCBI
35	Tho LL, Lee WH and Candlish JK: Erythrocytic enzymes decomposing reactive oxygen species and glucose 6-phosphate dehydrogenase deficiency. Singapore Med J. 29:60–62. 1988.PubMed/NCBI
36	Cai T, Kuang Y, Zhang C, Zhang Z, Chen L, Li B, Li Y, Wang Y, Yang H, Han Q and Zhu Y: Glucose-6-phosphate dehydrogenase and NADPH oxidase 4 control STAT3 activity in melanoma cells through a pathway involving reactive oxygen species, c-SRC and SHP2. Am J Cancer Res. 5:1610–1620. 2015.PubMed/NCBI
37	Nadeem A, Al-Harbi NO, Ahmad SF, Ibrahim KE, Siddiqui N and Al-Harbi MM: Glucose-6-phosphate dehydrogenase inhibition attenuates acute lung injury through reduction in NADPH oxidase-derived reactive oxygen species. Clin Exp Immunol. 191:279–287. 2018. View Article : Google Scholar : PubMed/NCBI
38	Coda DM, Lingua MF, Morena D, Foglizzo V, Bersani F, Ala U, Ponzetto C and Taulli R: SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma. Cell Cycle. 14:1389–1402. 2015. View Article : Google Scholar : PubMed/NCBI
39	Hu T, Chang YF, Xiao Z, Mao R, Tong J, Chen B, Liu GC, Hong Y, Chen HL, Kong SY, et al: miR-1 inhibits progression of high-risk papillomavirus-associated human cervical cancer by targeting G6PD. Oncotarget. 7:86103–86116. 2016. View Article : Google Scholar : PubMed/NCBI
40	Wang L, Yuan Y, Li J, Ren H, Cai Q, Chen X, Liang H, Shan H, Fu ZD, Gao X, et al: MicroRNA-1 aggravates cardiac oxidative stress by post-transcriptional modification of the antioxidant network. Cell Stress Chaperones. 20:411–420. 2015. View Article : Google Scholar : PubMed/NCBI
41	Gelman SJ, Naser F, Mahieu NG, McKenzie LD, Dunn GP, Chheda MG and Patti GJ: Consumption of NADPH for 2-HG synthesis increases pentose phosphate pathway flux and sensitizes cells to oxidative stress. Cell Rep. 22:512–522. 2018. View Article : Google Scholar : PubMed/NCBI
42	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
43	Han C, Zhou Y, An Q, Li F, Li D, Zhang X, Yu Z, Zheng L, Duan Z and Kan Q: MicroRNA-1 (miR-1) inhibits gastric cancer cell proliferation and migration by targeting MET. Tumour Biol. 36:6715–6723. 2015. View Article : Google Scholar : PubMed/NCBI
44	Liu R, Li J, Lai Y, Liao Y, Liu R and Qiu W: Hsa-miR-1 suppresses breast cancer development by down-regulating K-ras and long non-coding RNA MALAT1. Int J Biol Macromol. 81:491–497. 2015. View Article : Google Scholar : PubMed/NCBI
45	Xu W, Zhang Z, Zou K, Cheng Y, Yang M, Chen H, Wang H, Zhao J, Chen P, He L, et al: MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell Death Dis. 8:e27612017. View Article : Google Scholar : PubMed/NCBI
46	Peng CY, Liao YW, Lu MY, Yu CH, Yu CC and Chou MY: Downregulation of miR-1 enhances tumorigenicity and invasiveness in oral squamous cell carcinomas. J Formos Med Assoc. 116:782–789. 2017. View Article : Google Scholar : PubMed/NCBI
47	Qu W, Chen X, Wang J, Lv J and Yan D: MicroRNA-1 inhibits ovarian cancer cell proliferation and migration through c-Met pathway. Clin Chim Acta. 473:237–244. 2017. View Article : Google Scholar : PubMed/NCBI
48	Xie M, Dart DA, Guo T, Xing XF, Cheng XJ, Du H, Jiang WG, Wen XZ and Ji JF: MicroRNA-1 acts as a tumor suppressor microRNA by inhibiting angiogenesis-related growth factors in human gastric cancer. Gastric Cancer. 21:41–54. 2018. View Article : Google Scholar : PubMed/NCBI
49	Yu Q, Liu Y, Wen C, Zhao Y, Jin S, Hu Y, Wang F, Chen L, Zhang B, Wang W, et al: MicroRNA-1 inhibits tumorigenicity of esophageal squamous cell carcinoma and enhances sensitivity to gefitinib. Oncol Lett. 15:963–971. 2018.PubMed/NCBI
50	Wang X, Li X, Zhang X, Fan R, Gu H, Shi Y and Liu H: Glucose-6-phosphate dehydrogenase expression is correlated with poor clinical prognosis in esophageal squamous cell carcinoma. Eur J Surg Oncol. 41:1293–1299. 2015. View Article : Google Scholar : PubMed/NCBI
51	Pu H, Zhang Q, Zhao C, Shi L, Wang Y, Wang J and Zhang M: Overexpression of G6PD is associated with high risks of recurrent metastasis and poor progression-free survival in primary breast carcinoma. World J Surg Oncol. 13:3232015. View Article : Google Scholar : PubMed/NCBI
52	Lu M, Lu L, Dong Q, Yu G, Chen J, Qin L, Wang L, Zhu W and Jia H: Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition. Acta Biochim Biophys Sin. 50:370–380. 2018. View Article : Google Scholar : PubMed/NCBI
53	Wang X, Wu G, Cao G, Yang L, Xu H, Huang J and Hou J: Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells. Mol Med Rep. 12:4620–4625. 2015. View Article : Google Scholar : PubMed/NCBI
54	Jiang P, Du W and Yang X: A critical role of glucose-6-phosphate dehydrogenase in TAp73-mediated cell proliferation. Cell Cycle. 12:3720–3726. 2013. View Article : Google Scholar : PubMed/NCBI