Long non‑coding RNA CACNA1G‑AS1 promotes calcium channel protein expression and positively affects human keloid fibroblast migration

Li,Ye; Liang,Xuebing; Wang,Peng; Long,Xiao; Wang,Xiaojun; Meng,Zhiqiang

doi:10.3892/ol.2018.8717

Long non‑coding RNA CACNA1G‑AS1 promotes calcium channel protein expression and positively affects human keloid fibroblast migration

Authors:
- Ye Li
- Xuebing Liang
- Peng Wang
- Xiao Long
- Xiaojun Wang
- Zhiqiang Meng
View Affiliations

Affiliations: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
Published online on: May 16, 2018 https://doi.org/10.3892/ol.2018.8717
Pages: 891-897
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Keloids are a type of benign hyperplasia that cause dermatologic dysfunction and esthetic deformity by invading adjacent normal tissues. Little is known about their etiology, therefore, they are a challenge to treat using plastic surgery. In a previous study, it was demonstrated that the expression of the long non‑coding RNA CACNA1G‑AS1 (CAS1) is high in keloid tissue, suggesting that CAS1 is involved in keloid formation. In the present study, the aim was to identify potential keloid target proteins by exploring CAS1 biological function during cell proliferation and migration, cytokine secretion, collagen secretion and the control of calcium channel protein expression in human keloid fibroblasts. Three biopsy samples were collected from each patient with keloids at The Peking Union Medical College Hospital, which were then used to investigate the role of CAS1 in cell proliferation and migration. CAS1 silencing was also carried out using small interfering RNA; cell factors, collagen and calcium channel protein levels were compared with control cells. The interference of CAS1 expression reached 50% compared with the control group. CACNA1G and type I collagen expression was significantly downregulated by CAS1 knockdown, while the expression of transforming growth factor‑β and type III collagen was not affected. Wound healing time was longer in the CAS1‑knockdown group, but there was no visible change in cell proliferation. In conclusion, CAS1 appeared to promote calcium channel protein and type I collagen expression, and to have a positive effect on cell migration in human keloid fibroblasts. Therefore it has potential as a novel therapeutic target for keloids.

View Figures

View References

1	Robles DT and Berg D: Abnormal wound healing: Keloids. Clin Dermatol. 25:26–32. 2007. View Article : Google Scholar : PubMed/NCBI
2	Sun LM, Wang KH and Lee YC: Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: A nationwide population-based study. Arch Dermatol Res. 306:803–808. 2014. View Article : Google Scholar : PubMed/NCBI
3	Huang C, Murphy GF, Akaishi S and Ogawa R: Keloids and hypertrophic scars: Update and future directions. Plast Reconstr Surg Glob Open. 1:e252013. View Article : Google Scholar : PubMed/NCBI
4	Bock O, Schmid-Ott G, Malewski P and Mrowietz U: Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res. 297:433–438. 2006. View Article : Google Scholar : PubMed/NCBI
5	Ud-Din S, Volk SW and Bayat A: Regenerative healing, scar-free healing and scar formation across the species: Current concepts and future perspectives. Exp Dermatol. 23:615–619. 2014. View Article : Google Scholar : PubMed/NCBI
6	Lee JY, Yang CC, Chao SC and Wong TW: Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol. 26:379–384. 2004. View Article : Google Scholar : PubMed/NCBI
7	Huang C, Akaishi S, Hyakusoku H and Ogawa R: Are keloid and hypertrophic scar different forms of the same disorder? A fibroproliferative skin disorder hypothesis based on keloid findings. Int Wound J. 11:517–522. 2014. View Article : Google Scholar : PubMed/NCBI
8	Mofikoya BO, Adeyemo WL and Abdus-salam AA: Keloid and hypertrophic scars: A review of recent developments in pathogenesis and management. Nig Q J Hosp Med. 17:134–139. 2007.PubMed/NCBI
9	Ogawa R, Okai K, Tokumura F, Mori K, Ohmori Y, Huang C, Hyakusoku H and Akaishi S: The relationship between skin stretching/contraction and pathologic scarring: The important role of mechanical forces in keloid generation. Wound Repair Regen. 20:149–157. 2012. View Article : Google Scholar : PubMed/NCBI
10	Naylor MC and Brissett AE: Current concepts in the etiology and treatment of keloids. Facial Plast Surg. 28:504–512. 2012. View Article : Google Scholar : PubMed/NCBI
11	Jin Z: Increased c-Met phosphorylation is related to keloid pathogenesis: Implications for the biological behaviour of keloid fibroblasts. Pathology. 46:25–31. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ogawa R, Akaishi S, Huang C, Dohi T, Aoki M, Omori Y, Koike S, Kobe K, Akimoto M and Hyakusoku H: Clinical applications of basic research that shows reducing skin tension could prevent and treat abnormal scarring: The importance of fascial/subcutaneous tensile reduction sutures and flap surgery for keloid and hypertrophic scar reconstruction. J Nippon Med Sch. 78:68–76. 2011. View Article : Google Scholar : PubMed/NCBI
13	Akaishi S, Akimoto M, Ogawa R and Hyakusoku H: The relationship between keloid growth pattern and stretching tension: Visual analysis using the finite element method. Ann Plast Surg. 60:445–451. 2008. View Article : Google Scholar : PubMed/NCBI
14	Nakashima M, Chung S, Takahashi A, Kamatani N, Kawaguchi T, Tsunoda T, Hosono N, Kubo M, Nakamura Y and Zembutsu H: A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat Genet. 42:768–771. 2010. View Article : Google Scholar : PubMed/NCBI
15	Arima J, Huang C, Rosner B, Akaishi S and Ogawa R: Hypertension: A systemic key to understanding local keloid severity. Wound Repair Regen. 23:213–221. 2015. View Article : Google Scholar : PubMed/NCBI
16	Park TH and Chang CH: Keloid recurrence in pregnancy. Aesthetic Plast Surg. 36:1271–1272. 2012. View Article : Google Scholar : PubMed/NCBI
17	Fong EP and Bay BH: Keloids-the sebum hypothesis revisited. Med Hypotheses. 58:264–269. 2002. View Article : Google Scholar : PubMed/NCBI
18	Ichioka S, Ando T, Shibata M, Sekiya N and Nakatsuka T: Oxygen consumption of keloids and hypertrophic scars. Ann Plast Surg. 60:194–197. 2008. View Article : Google Scholar : PubMed/NCBI
19	Liang X, Ma L, Long X and Wang X: LncRNA expression profiles and validation in keloid and normal skin tissue. Int J Oncol. 47:1829–1838. 2015. View Article : Google Scholar : PubMed/NCBI
20	Russell SB, Russell JD, Trupin KM, Gayden AE, Opalenik SR, Nanney LB, Broquist AH, Raju L and WIlliams SM: Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol. 130:24892010. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Gibb EA, Brown CJ and Lam WL: The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 10:382011. View Article : Google Scholar : PubMed/NCBI
23	Vance KW and Ponting CP: Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet. 30:348–355. 2014. View Article : Google Scholar : PubMed/NCBI
24	Kung JT, Colognori D and Lee JT: Long noncoding RNAs: Past, present, and future. Genetics. 193:651–669. 2013. View Article : Google Scholar : PubMed/NCBI
25	Prensner JR and Chinnaiyan AM: The emergence of lncRNAs in cancer biology. Cancer Discov. 1:391–407. 2011. View Article : Google Scholar : PubMed/NCBI
26	Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS and Perera RJ: The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res. 71:3852–3862. 2011. View Article : Google Scholar : PubMed/NCBI
27	Tang L, Zhang W, Su B and Yu B: Long noncoding RNA HOTAIR is associated with motility, invasion, and metastatic potential of metastatic melanoma. Biomed Res Int. 2013:2510982013. View Article : Google Scholar : PubMed/NCBI
28	He Y, Wu YT, Huang C, Meng XM, Ma TT, Wu BM, Xu FY, Zhang L, Lv XW and Li J: Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis. Biochim Biophys Acta. 1842:2204–2215. 2014. View Article : Google Scholar : PubMed/NCBI
29	Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J and Guo H: TGFβ1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep. 5:119242015. View Article : Google Scholar : PubMed/NCBI
30	Fukunaga K: Cognitive function and calcium. Cognitive improvement through T type calcium channel stimulation. Clin Calcium. 25:247–254. 2015.(In Japanese). PubMed/NCBI
31	Yuan SX, Tao QF, Wang J, Yang F, Liu L, Wang LL, Zhang J, Yang Y, Liu H, Wang F, et al: Antisense long non-coding RNA PCNA-AS1 promotes tumor growth by regulating proliferating cell nuclear antigen in hepatocellular carcinoma. Cancer Lett. 349:87–94. 2014. View Article : Google Scholar : PubMed/NCBI
32	D'Andrea F, Brongo S, Ferraro G and Baroni A: Prevention and treatment of keloids with intralesional verapamil. Dermatology. 204:60–62. 2002. View Article : Google Scholar : PubMed/NCBI
33	Wang R, Mao Y, Zhang Z, Li Z, Chen J and Cen Y: Role of verapamil in preventing and treating hypertrophic scars and keloids. Int Wound J. 13:461–468. 2016. View Article : Google Scholar : PubMed/NCBI
34	Alexandrescu D, Fabi S, Yeh LC, Fitzpatrick RE and Goldman MP: Comparative results in treatment of keloids with intralesional 5-FU/Kenalog, 5-FU/Verapamil, Enalapril Alone, verapamil alone, and laser: A case report and review of the literature. J Drugs Dermatol. 15:1442–1447. 2016.PubMed/NCBI
35	Grossman E and Messerli FH: Calcium antagonists. Prog Cardiovasc Dis. 47:34–57. 2004. View Article : Google Scholar : PubMed/NCBI
36	Lee RC, Doong H and Jellema AF: The response of burn scars to intralesional verapamil. Report of five cases. Arch Surg. 129:107–111. 1994. View Article : Google Scholar : PubMed/NCBI
37	Doong H, Dissanayake S, Gowrishankar TR, LaBarbera MC and Lee RC: The 1996 Lindberg Award. Calcium antagonists alter cell shape and induce procollagenase synthesis in keloid and normal human dermal fibroblasts. J Burn Care Rehabil. 17:497–514. 1996. View Article : Google Scholar : PubMed/NCBI
38	Lee RC and Ping JA: Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J Surg Res. 49:463–466. 1990. View Article : Google Scholar : PubMed/NCBI
39	Giugliano G, Pasquali D, Notaro A, Brongo S, Nicoletti G, D'Andrea F, Bellastella A and Sinisi AA: Verapamil inhibits interleukin-6 and vascular endothelial growth factor production in primary cultures of keloid fibroblasts. Br J Plast Surg. 56:804–809. 2003. View Article : Google Scholar : PubMed/NCBI
40	Xu SJ, Teng JY, Xie J, Shen MQ and Chen DM: Comparison of the mechanisms of intralesional steroid, interferon or verapamil injection in the treatment of proliferative scars. Zhonghua Zheng Xing Wai Ke Za Zhi. 25:37–40. 2009.(In Chinese). PubMed/NCBI