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Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer

Oncogene volume 33, pages 3636–3647 (2014)Cite this article

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Abstract

miR-126 is an endothelial-specific microRNA essential for maintaining vessel integrity during development. Its role of tumor angiogenesis in cancer stroma is unclear. This study investigated the temporal and spatial expression and the role of miR-126 in the course of cervical carcinogenesis. miR-126 was found to be mainly expressed in the stromal endothelium of the uterine cervix. This downregulation was recapitulated in a cell coculture model, wherein cross talk of cervical cancer cells and fibroblasts induced a downregulation of miR-126 in human umbilical vein endothelial cells, with consequent increase of tube formation. Coinjection of cancer-associated fibroblasts of human cervix enhanced tumorigenesis of cervical cancer cells, with an increase of microvessel density and dye retention in the tumor vasculature. In association with angiogenesis, host-originated miR-126 in these xenograft tumors was progressively downregulated, whereas supplement of the miR-126 precursor in the coinjection suppressed angiogenesis and tumor growth. A proangiogenic gene adrenomedullin (ADM), which was found to be upregulated in the stroma of cervical cancer and which localized mainly in the blood and lymphatic vessels, was identified as a target of inhibition by miR-126 at the carcinoma in situ-to-invasion stage. The study suggests a cancer stroma cross talk induced repression of miR-126 and upregulation of ADM, and probably other proangiogenic factors, to facilitate angiogenesis and invasion growth of cervical cancer.

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References

  1. Bhowmick NA, Moses HL . Tumor-stroma interactions. Curr Opin Genet Dev 2005; 15: 97–101.

    Article  CAS  Google Scholar 

  2. Dellas A, Moch H, Schultheiss E, Feichter G, Almendral AC, Gudat F et al. Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations. Gynecol Oncol 1997; 67: 27–33.

    Article  CAS  Google Scholar 

  3. Dobbs SP, Hewett PW, Johnson IR, Carmichael J, Murray JC . Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia. Br J Cancer 1997; 76: 1410–1415.

    Article  CAS  Google Scholar 

  4. Guidi AJ, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst 1995; 87: 1237–1245.

    Article  CAS  Google Scholar 

  5. Cintorino M, Bellizzi de Marco E, Leoncini P, Tripodi SA, Xu LJ, Sappino AP et al. Expression of alpha-smooth-muscle actin in stromal cells of the uterine cervix during epithelial neoplastic changes. Int J Cancer 1991; 47: 843–846.

    Article  CAS  Google Scholar 

  6. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    Article  CAS  Google Scholar 

  7. Urbich C, Kuehbacher A, Dimmeler S . Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 2008; 79: 581–588.

    Article  CAS  Google Scholar 

  8. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008; 15: 272–284.

    Article  CAS  Google Scholar 

  9. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 2008; 15: 261–271.

    Article  Google Scholar 

  10. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ . MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA 2008; 105: 1516–1521.

    Article  CAS  Google Scholar 

  11. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009; 2: ra81.

    Article  Google Scholar 

  12. Guo C, Sah JF, Beard L, Willson JK, Markowitz SD, Guda K . The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer 2008; 47: 939–946.

    Article  CAS  Google Scholar 

  13. Hamada S, Satoh K, Fujibuchi W, Hirota M, Kanno A, Unno J et al. MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol Cancer Res 2012; 10: 3–10.

    Article  CAS  Google Scholar 

  14. Feng R, Chen X, Yu Y, Su L, Yu B, Li J et al. miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett 2010; 298: 50–63.

    Article  CAS  Google Scholar 

  15. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008; 451: 147–152.

    Article  CAS  Google Scholar 

  16. Sun Y, Bai Y, Zhang F, Wang Y, Guo Y, Guo L . miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem Biophys Res Commun 2010; 391: 1483–1489.

    Article  CAS  Google Scholar 

  17. Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, Khan SA . Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene 2008; 27: 2575–2582.

    Article  CAS  Google Scholar 

  18. Lee JW, Choi CH, Choi JJ, Park YA, Kim SJ, Hwang SY et al. Altered MicroRNA expression in cervical carcinomas. Clin Cancer Res 2008; 14: 2535–2542.

    Article  CAS  Google Scholar 

  19. Kato H, Shichiri M, Marumo F, Hirata Y . Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 1997; 138: 2615–2620.

    Article  CAS  Google Scholar 

  20. Ribatti D, Nico B, Spinazzi R, Vacca A, Nussdorfer GG . The role of adrenomedullin in angiogenesis. Peptides 2005; 26: 1670–1675.

    Article  CAS  Google Scholar 

  21. Liu B, Peng XC, Zheng XL, Wang J, Qin YW . MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer 2009; 66: 169–175.

    Article  Google Scholar 

  22. Sasahira T, Kurihara M, Bhawal UK, Ueda N, Shimomoto T, Yamamoto K et al. Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. Br J Cancer 2012; 107: 700–706.

    Article  CAS  Google Scholar 

  23. Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 2003; 63: 3403–3412.

    CAS  Google Scholar 

  24. Bai Y, Bai X, Wang Z, Zhang X, Ruan C, Miao J . MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors. Exp Mol Pathol 2011; 91: 471–477.

    Article  CAS  Google Scholar 

  25. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993; 192: 553–560.

    Article  CAS  Google Scholar 

  26. Karpinich NO, Hoopes SL, Kechele DO, Lenhart PM, Caron KM . Adrenomedullin function in vascular endothelial cells: insights from genetic mouse models. Curr Hypertens Rev 2011; 7: 228–239.

    Article  CAS  Google Scholar 

  27. Nikitenko LL, Fox SB, Kehoe S, Rees MC, Bicknell R . Adrenomedullin and tumour angiogenesis. Br J Cancer 2006; 94: 1–7.

    Article  CAS  Google Scholar 

  28. Frede S, Freitag P, Otto T, Heilmaier C, Fandrey J . The proinflammatory cytokine interleukin 1beta and hypoxia cooperatively induce the expression of adrenomedullin in ovarian carcinoma cells through hypoxia inducible factor 1 activation. Cancer Res 2005; 65: 4690–4697.

    Article  CAS  Google Scholar 

  29. Karpinich NO, Kechele DO, Espenschied ST, Willcockson HH, Fedoriw Y, Caron KM . Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J 2013; 27: 590–600.

    Article  CAS  Google Scholar 

  30. Iwase T, Nagaya N, Fujii T, Itoh T, Ishibashi-Ueda H, Yamagishi M et al. Adrenomedullin enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia. Circulation 2005; 111: 356–362.

    Article  CAS  Google Scholar 

  31. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999; 144: 789–801.

    Article  CAS  Google Scholar 

  32. Cooley LS, Handsley MM, Zhou Z, Lafleur MA, Pennington CJ, Thompson EW et al. Reversible transdifferentiation of blood vascular endothelial cells to a lymphatic-like phenotype in vitro. J Cell Sci 2010; 123: 3808–3816.

    Article  CAS  Google Scholar 

  33. McCall MN, Kent OA, Yu J, Fox-Talbot K, Zaiman AL, Halushka MK . MicroRNA profiling of diverse endothelial cell types. BMC Med Genomics 2011; 4: 78.

    Article  CAS  Google Scholar 

  34. Botting SK, Fouad H, Elwell K, Rampy BA, Salama SA, Freeman DH et al. Prognostic significance of peritumoral lymphatic vessel density and vascular endothelial growth factor receptor 3 in invasive squamous cell cervical cancer. Transl Oncol 2010; 3: 170–175.

    Article  Google Scholar 

  35. Zhu N, Zhang D, Xie H, Zhou Z, Chen H, Hu T et al. Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol Cell Biochem 2011; 351: 157–164.

    Article  CAS  Google Scholar 

  36. Wang KH, Liu HW, Lin SR, Ding DC, Chu TY . Field methylation silencing of the protocadherin 10 gene in cervical carcinogenesis as a potential specific diagnostic test from cervical scrapings. Cancer Sci 2009; 100: 2175–2180.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ms Yen-Jen Shih for the technical assistance. We also thank Dr Lu-Hai Wang for his comments during the preparation of this manuscript. Ted Knoy is appreciated for his editorial assistance. This study was supported by the National Science Council of the Republic of China, Taiwan (contract number NSC 97-2314-B-303-008-MY3) and by the Buddhist Tzu Chi General Hospital, Hualien, Taiwan (contract number TCRD100-54-01).

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Authors and Affiliations

  1. Department of Research, Center for Cervical Cancer Prevention, Tzu Chi General Hospital, Hualien, Taiwan, ROC

    T-H Huang & T-Y Chu

  2. Institute of Medical Science, Tzu Chi University, Hualien, Taiwan, ROC

    T-H Huang & T-Y Chu

  3. Department of Obstetrics and Gynecology, Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC

    T-Y Chu

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  1. T-H Huang
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Correspondence to T-Y Chu.

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Huang, TH., Chu, TY. Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer. Oncogene 33, 3636–3647 (2014). https://doi.org/10.1038/onc.2013.335

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