Abstract
Previous studies have demonstrated the involvement of long intergenic nonprotein coding RNA 173 (LINC00173) in several pathological disorders. However, the function of LINC00173 in the hypertrophic scar is not well understood. This study confirmed that the two transcript variants of TSV1 and TSV2 were both upregulated in hypertrophic scar fibroblasts. The overexpression of TSV1 or TSV2 promoted the apoptosis of fibroblasts, whereas the overexpression of TSV2 inhibited the proliferation of fibroblasts. RNA-sequencing (RNA-seq), Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA) showed that phosphatidylinositol 3-kinase (PI3K)/Akt and Mitogen-activated protein kinases (MAPK) signaling might be involved in the role of LINC00173 in hypertrophic scar pathogenesis. Furthermore, the protein expression of β-catenin was upregulated in the TSV1 or TSV2 overexpression group. Overall, the study demonstrated that LINC00173 promoted the apoptosis of fibroblasts through increasing β-catenin expression, suggesting that LINC00173 might be a new target for hypertrophic scar treatment.
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References
Berman B, Maderal A, Raphael B (2017) Keloids and hypertrophic scars: pathophysiology, classification, and treatment. Dermatol Surg 43(Suppl 1):S3–S18
Lee HJ, Jang YJ (2018) Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. Int J Mol Sci 19(3):711
Liang X, Chai B, Duan R, Zhou Y, Huang X, Li Q (2017) Inhibition of FKBP10 attenuates hypertrophic scarring through suppressing fibroblast activity and extracellular matrix deposition. J Invest Dermatol 137(11):2326–2335
Xiao Y, Xu D, Song H, Shu F, Wei P, Yang X, Zhong C, Wang X, Muller WE, Zheng Y, Xiao S, Xia Z (2019) Cuprous oxide nanoparticles reduces hypertrophic scarring by inducing fibroblast apoptosis. Int J Nanomedicine 14:5989–6000
Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172(3):393–407
Tu L, Huang Q, Fu S, Liu D (2018) Aberrantly expressed long noncoding RNAs in hypertrophic scar fibroblasts in vitro: a microarray study. Int J Mol Med 41(4):1917–1930
Li M, Wang J, Liu D, Huang H (2018) Highthroughput sequencing reveals differentially expressed lncRNAs and circRNAs, and their associated functional network, in human hypertrophic scars. Mol Med Rep 18(6):5669–5682
Chen J, Zhou R, Liang Y, Fu X, Wang D, Wang C (2019) Blockade of lncRNA-ASLNCS5088-enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J 33(11):12200–12212
Nong Q, Li S, Wu Y, Liu D (2018) LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR-21/Smad7 pathway. Biochem Biophys Res Commun 495(1):319–324
Li J, Chen L, Cao C, Yan H, Zhou B, Gao Y, Li Q, Li J (2016) The long non-coding RNA LncRNA8975-1 is upregulated in hypertrophic scar fibroblasts and controls collagen expression. Cell Physiol Biochem 40(1–2):326–334
Postler TS, Pantry SN, Desrosiers RC, Ghosh S (2017) Identification and characterization of a long non-coding RNA up-regulated during HIV-1 infection. Virology 511:30–39
Schwarzer A, Emmrich S, Schmidt F, Beck D, Ng M, Reimer C, Adams FF, Grasedieck S, Witte D, Kabler S, Wong JWH, Shah A, Huang Y, Jammal R, Maroz A, Jongen-Lavrencic M, Schambach A, Kuchenbauer F, Pimanda JE, Reinhardt D, Heckl D, Klusmann JH (2017) The non-coding RNA landscape of human hematopoiesis and leukemia. Nat Commun 8(1):218
Mao Y, Fu Z, Zhang Y, Dong L, Zhang Y, Zhang Q, Li X, Liu J (2018) A seven-lncRNA signature predicts overall survival in esophageal squamous cell carcinoma. Sci Rep 8(1):8823
Hu Z, Yang D, Tang Y, Zhang X, Wei Z, Fu H, Xu J, Zhu Z, Cai Q (2019) Five-long non-coding RNA risk score system for the effective prediction of gastric cancer patient survival. Oncol Lett 17(5):4474–4486
Zeng F, Wang Q, Wang S, Liang S, Huang W, Guo Y, Peng J, Li M, Zhu W, Guo L (2020) Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression. Oncogene 39(2):293–307
Yang Q, Tang Y, Tang C, Cong H, Wang X, Shen X, Ju S (2019) Diminished LINC00173 expression induced miR-182-5p accumulation promotes cell proliferation, migration and apoptosis inhibition via AGER/NF-kappaB pathway in non-small-cell lung cancer. Am J Transl Res 11(7):4248–4262
Chen L, Li Q, Lu X, Dong X, Li J (2019) Overexpression of miR-340-5p inhibits skin fibroblast proliferation by targeting Kruppel-like factor 2. Curr Pharm Biotechnol 20(13):1147–1154
Chen L, Li J, Li Q, Li X, Gao Y, Hua X, Zhou B, Li J (2018) Overexpression of LncRNA AC067945.2 down-regulates collagen expression in skin fibroblasts and possibly correlates with the VEGF and Wnt signalling pathways. Cell Physiol Biochem 45(2):761–771
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550
Torii K, Nishizawa K, Kawasaki A, Yamashita Y, Katada M, Ito M, Nishimoto I, Terashita K, Aiso S, Matsuoka M (2008) Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways. Cell Signal 20(7):1256–1266
Dees C, Distler JH (2013) Canonical Wnt signalling as a key regulator of fibrogenesis – implications for targeted therapies? Exp Dermatol 22(11):710–713
Honardoust D, Ding J, Varkey M, Shankowsky HA, Tredget EE (2012) Deep dermal fibroblasts refractory to migration and decorin-induced apoptosis contribute to hypertrophic scarring. J Burn Care Res 33(5):668–677
Wang J, Dodd C, Shankowsky HA, Scott PG, Tredget EE, G. Wound Healing Research (2008) Deep dermal fibroblasts contribute to hypertrophic scarring. Lab Investig 88(12):1278–1290
Chen L, Li J, Li Q, Yan H, Zhou B, Gao Y, Li J (2017) Non-coding RNAs: the new insight on hypertrophic scar. J Cell Biochem 118(8):1965–1968
Liao WT, Yu HS, Arbiser JL, Hong CH, Govindarajan B, Chai CY, Shan WJ, Lin YF, Chen GS, Lee CH (2010) Enhanced MCP-1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP-1 and Akt pathway in keloids. Exp Dermatol 19(8):e142–e150
Dey JH, Bianchi F, Voshol J, Bonenfant D, Oakeley EJ, Hynes NE (2010) Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res 70(10):4151–4162
Zhang X, Lan D, Ning S, Jia H, Yu S (2019) Botulinum toxin type A prevents the phenotypic transformation of fibroblasts induced by TGFbeta1 via the PTEN/PI3K/Akt signaling pathway. Int J Mol Med 44(2):661–671
Yang F, Chen E, Yang Y, Han F, Han S, Wu G, Zhang M, Zhang J, Han J, Su L, Hu D (2019) The Akt/FoxO/p27(Kip1) axis contributes to the anti-proliferation of pentoxifylline in hypertrophic scars. J Cell Mol Med 23(9):6164–6172
Chen JY, Zhang L, Zhang H, Su L, Qin LP (2014) Triggering of p38 MAPK and JNK signaling is important for oleanolic acid-induced apoptosis via the mitochondrial death pathway in hypertrophic scar fibroblasts. Phytother Res 28(10):1468–1478
Li Y, Zhang W, Gao J, Liu J, Wang H, Li J, Yang X, He T, Guan H, Zheng Z, Han S, Dong M, Han J, Shi J, Hu D (2016) Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway. Stem Cell Res Ther 7(1):102
Sato M (2006) Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids. Acta Derm Venereol 86(4):300–307
Kim KI, Jeong DS, Yoon TJ, Jung EC, Lee JH, Kim CD (2017) Inhibition of collagen production by ICG-001, a small molecule inhibitor for Wnt/beta-catenin signaling, in skin fibroblasts. J Dermatol Sci 86(1):76–78
Acknowledgements
This study was supported by the National Natural Science Foundation of China (81701910); the Jiangsu Maternal and Child Health Research Project (F201608); and the Science and Technology Development Foundation of Nanjing Medical University (2017NJMUZD065).
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Jun Li projected the experiment. Qian Li and Xin Chen performed the cell transfection and qRT-PCR experiments. Ling Chen and Hui Yan performed the bioinformatics analysis the statistical analysis. Jun Li wrote and edited the manuscript.
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Li, Q., Chen, X., Chen, L. et al. LINC00173 promotes the apoptosis of hypertrophic scar fibroblasts through increasing β-catenin expression. Mol Cell Biochem 476, 1005–1014 (2021). https://doi.org/10.1007/s11010-020-03966-6
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DOI: https://doi.org/10.1007/s11010-020-03966-6