Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6

Xu,Xiaofang; Ge,Shengfang; Jia,Renbing; Zhou,Yixiong; Song,Xin; Zhang,He; Fan,Xianqun

doi:10.3892/or.2015.3900

Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6

Authors:
- Xiaofang Xu
- Shengfang Ge
- Renbing Jia
- Yixiong Zhou
- Xin Song
- He Zhang
- Xianqun Fan
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Affiliations: Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: April 7, 2015 https://doi.org/10.3892/or.2015.3900
Pages: 2789-2796

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Abstract

Previous findings showed that miR-181b is upregulated under hypoxic conditions in retinoblastoma cells. Since hypoxia is a common feature of retinoblastoma that affects tumor progression as well as tumor therapy, in the present study, we investigated the regulatory mechanism of miR-181b under hypoxic conditions, and examined the role of miR-181b in retinoblastoma responses to hypoxia (chemoresistance and angiogenesis) and possible downstream genes. The level of hypoxia-inducible factor-1α (HIF-1α) and miR-181b was detected to examine the link between them. Tube formation and cell cytotoxicity assays were used to clarify the effects of miR-181b on hypoxic responses of retinoblastoma cells. Bioinformatics analysis was performed to predict potential targets of miR-181b and western blotting was used to verify these targets. The results showed a significantly increased expression of HIF-1α in hypoxia-treated retinoblastoma cells. Downregulation of HIF-1α using a small‑interfering RNA (siRNA) knockdown technology did not decrease the expression of miR-181b. Through gain- and loss-of-function studies, miR-181b was demonstrated to significantly stimulate the ability of capillary tube formation of endothelial cells. Programmed cell death-10 (PDCD10) and GATA binding protein 6 (GATA6) were identified as the target genes of miR‑181b. To the best of our knowledge, results of the present study provide the first evidence that miR-181b was upregulated by hypoxia in retinoblastoma in an HIF-1α-independent manner. miR-181b increased tumor angiogenesis of retinoblastoma cells. Additionally, miR-181b exerts its angiogenic function, at least in part, by inhibiting PDCD10 and GATA6. Thus, it is a new potentially useful therapeutic target for retinoblastoma.

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1	Kivelä T: The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 93:1129–1131. 2009. View Article : Google Scholar : PubMed/NCBI
2	Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE and Hurwitz R: Retinoblastoma: review of current management. Oncologist. 12:1237–1246. 2007. View Article : Google Scholar : PubMed/NCBI
3	Chantada GL, Qaddoumi I, Canturk S, Khetan V, Ma Z, Kimani K, Yeniad B, Sultan I, Sitorus RS, Tacyildiz N, et al: Strategies to manage retinoblastoma in developing countries. Pediatr Blood Cancer. 56:341–348. 2011. View Article : Google Scholar : PubMed/NCBI
4	Canturk S, Qaddoumi I, Khetan V, Ma Z, Furmanchuk A, Antoneli CB, Sultan I, Kebudi R, Sharma T, Rodriguez-Galindo C, et al: Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators. Br J Ophthalmol. 94:1432–1436. 2010. View Article : Google Scholar : PubMed/NCBI
5	Lee YJ, Lee JH, Moon JH and Park SY: Overcoming hypoxic resistance of tumor cells to TRAIL-induced apoptosis through melatonin. Int J Mol Sci. 15:11941–11956. 2014. View Article : Google Scholar : PubMed/NCBI
6	Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
7	Gruber M and Simon MC: Hypoxia-inducible factors, hypoxia, and tumor angiogenesis. Curr Opin Hematol. 13:169–174. 2006. View Article : Google Scholar : PubMed/NCBI
8	Greco S and Martelli F: MicroRNAs in hypoxia response. Antioxid Redox Signal. 21:1164–1166. 2014. View Article : Google Scholar : PubMed/NCBI
9	McCarthy N: Hypoxia: micro changes. Nat Rev Cancer. 14:382–383. 2014. View Article : Google Scholar : PubMed/NCBI
10	Qin Q, Furong W and Baosheng L: Multiple functions of hypoxia-regulated miR-210 in cancer. J Exp Clin Cancer Res. 33:502014. View Article : Google Scholar : PubMed/NCBI
11	Xu X, Jia R, Zhou Y, Song X, Wang J, Qian G, Ge S and Fan X: Microarray-based analysis: Identification of hypoxia-regulated microRNAs in retinoblastoma cells. Int J oncol. 38:1385–1393. 2011.PubMed/NCBI
12	Boutrid H, Jockovich ME, Murray TG, Piña Y, Feuer WJ, Lampidis TJ and Cebulla CM: Targeting hypoxia, a novel treatment for advanced retinoblastoma. Invest Ophthalmol Vis Sci. 49:2799–2805. 2008. View Article : Google Scholar : PubMed/NCBI
13	Lan KL, Lan KH, Sheu ML, Chen MY, Shih YS, Hsu FC, Wang HM, Liu RS and Yen SH: Honokiol inhibits hypoxia- inducible factor-1 pathway. Int J Radiat Biol. 87:579–590. 2011. View Article : Google Scholar : PubMed/NCBI
14	Tsai YP and Wu KJ: Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci. 19:1022012. View Article : Google Scholar : PubMed/NCBI
15	Voss MJ, Niggemann B, Zänker KS and Entschladen F: Tumour reactions to hypoxia. Curr Mol Med. 10:381–386. 2010. View Article : Google Scholar : PubMed/NCBI
16	Sudhakar J, Venkatesan N, Lakshmanan S, Khetan V, Krishnakumar S and Biswas J: Hypoxic tumor microenvironment in advanced retinoblastoma. Pediatr Blood Cancer. 60:1598–1601. 2013. View Article : Google Scholar : PubMed/NCBI
17	Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, Kong D, Sethi S, Aboukameel A, Padhye SB, et al: Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One. 7:e501652012. View Article : Google Scholar : PubMed/NCBI
18	Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, et al: A microRNA signature of hypoxia. Mol Cell Biol. 27:1859–1867. 2007. View Article : Google Scholar :
19	He L, He X, Lim LP, De Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, et al: A microRNA component of the p53 tumour suppressor network. Nature. 447:1130–1134. 2007. View Article : Google Scholar : PubMed/NCBI
20	Sermeus A and Michiels C: Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2:e1642011. View Article : Google Scholar : PubMed/NCBI
21	Kluiver J, van den Berg A, De Jong D, Blokzijl T, Harms G, Bouwman E, Jacobs S, Poppema S and Kroesen BJ: Regulation of pri-microRNA BIC transcription and processing in Burkitt lymphoma. Oncogene. 26:3769–3776. 2007. View Article : Google Scholar
22	Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, Pyronnet S, Kaufman RJ, Weppler SA, Voncken JW, et al: Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 25:1114–1125. 2006. View Article : Google Scholar : PubMed/NCBI
23	Zhao L and Ackerman SL: Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol. 18:444–452. 2006. View Article : Google Scholar : PubMed/NCBI
24	Xi Y, Formentini A, Chien M, Weir DB, Russo JJ and Ju J, Kornmann M and Ju J: Prognostic values of microRNAs in colorectal cancer. Biomark Insights. 2:113–121. 2006.
25	Nakajima G, Hayashi K, Xi Y, Kudo K, Uchida K, Takasaki K, Yamamoto M and Ju J: Non-coding MicroRNAs hsa-let-7g and hsa-miR-181b are associated with chemoresponse to S-1 in colon cancer. Cancer Genomics Proteomics. 3:317–324. 2006.
26	Sun YC, Wang J, Guo CC, Sai K, Wang J, Chen FR, Yang QY, Chen YS, Wang J, To TS, et al: miR-181b sensitizes glioma cells to teniposide by targeting MDM2. BMC Cancer. 14:6112014. View Article : Google Scholar : PubMed/NCBI
27	Takiuchi D, Eguchi H, Nagano H, Iwagami Y, Tomimaru Y, Wada H, Kawamoto K, Kobayashi S, Marubashi S, Tanemura M, et al: Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells. Pancreatology. 13:517–523. 2013. View Article : Google Scholar : PubMed/NCBI
28	He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H and Min W: Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal. 3:ra262010. View Article : Google Scholar : PubMed/NCBI
29	Zhu Y, Wu Q, Xu JF, Miller D, Sandalcioglu IE, Zhang JM and Sure U: Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurg Focus. 29:E12010. View Article : Google Scholar : PubMed/NCBI
30	Schleider E, Stahl S, Wüstehube J, Walter U, Fischer A and Felbor U: Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3. Neurogenetics. 12:83–86. 2011. View Article : Google Scholar :
31	You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U and Zhu Y: Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med. 17:407–418. 2013. View Article : Google Scholar : PubMed/NCBI
32	Perlman H, Suzuki E, Simonson M, Smith RC and Walsh K: GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest. J Biol Chem. 273:13713–13718. 1998. View Article : Google Scholar : PubMed/NCBI
33	Crawford SE, Qi C, Misra P, Stellmach V, Rao MS, Engel JD, Zhu Y and Reddy JK: Defects of the heart, eye, and megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family of transcription factors. J Biol Chem. 277:3585–3592. 2002. View Article : Google Scholar
34	Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, Deng C, Wauthier E, Reid LM, Ye QH, et al: Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology. 50:472–480. 2009. View Article : Google Scholar : PubMed/NCBI