High expression of lncRNA <em>HSD11B1‑AS1</em> indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma

Liu,Kaiyuan; Zhang,Li; Li,Xiuli; Zhao,Jingjun

doi:10.3892/ol.2021.13172

High expression of lncRNA HSD11B1‑AS1 indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma

Authors:
- Kaiyuan Liu
- Li Zhang
- Xiuli Li
- Jingjun Zhao
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Affiliations: Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China, Department of Dermatology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
Published online on: December 20, 2021 https://doi.org/10.3892/ol.2021.13172
Article Number: 54
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non‑coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11β‑hydroxysteroid dehydrogenase type 1‑antisense RNA 1 (HSD11B1‑AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1‑AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1‑, 3‑ and 5‑year overall survival, progression‑free interval and disease‑specific survival. In vitro experiments verified the decreased HSD11B1‑AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit‑8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1‑AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN‑γ and ‑α response, TNF‑α signaling via NF‑κB and IL‑2/STAT‑5 and IL‑6/JAK/STAT‑3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1‑AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1‑AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.

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1	McCarthy M: US melanoma prevalence has doubled over past 30 years. BMJ. 350:h30742015. View Article : Google Scholar : PubMed/NCBI
2	Rebecca VW, Somasundaram R and Herlyn M: Pre-clinical modeling of cutaneous melanoma. Nat Commun. 11:28582020. View Article : Google Scholar : PubMed/NCBI
3	Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT and Davies MA: Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: A pooled analysis of individual patient data from randomised trials. Lancet Oncol. 17:1743–1754. 2016. View Article : Google Scholar : PubMed/NCBI
4	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
5	Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Bastholt L, Grob JJ, Malvehy J, Newton-Bishop J, Stratigos AJ, et al: Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline-Update 2016 = Eur J Cancer. 63:201–217. 2016.PubMed/NCBI
6	Luther C, Swami U, Zhang J, Milhem M and Zakharia Y: Advanced stage melanoma therapies: Detailing the present and exploring the future. Crit Rev Oncol Hematol. 133:99–111. 2019. View Article : Google Scholar : PubMed/NCBI
7	Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, et al: Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 375:819–829. 2016. View Article : Google Scholar : PubMed/NCBI
8	Liang Y, Song X, Li Y, Chen B, Zhao W, Wang L, Zhang H, Liu Y, Han D, Zhang N, et al: LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer. 19:852020. View Article : Google Scholar : PubMed/NCBI
9	Yu X, Zheng H, Tse G, Zhang L and Wu WKK: CASC2: An emerging tumour-suppressing long noncoding RNA in human cancers and melanoma. Cell Prolif. 51:e125062018. View Article : Google Scholar : PubMed/NCBI
10	Xu W, Yan Z, Hu F, Wei W, Yang C and Sun Z: Long non-coding RNA GAS5 accelerates oxidative stress in melanoma cells by rescuing EZH2-mediated CDKN1C downregulation. Cancer Cell Int. 20:1162020. View Article : Google Scholar : PubMed/NCBI
11	Yu X, Zheng H, Tse G, Chan MT and Wu WK: Long non-coding RNAs in melanoma. Cell Prolif. 51:e124572018. View Article : Google Scholar : PubMed/NCBI
12	Richtig G, Ehall B, Richtig E, Aigelsreiter A, Gutschner T and Pichler M: Function and clinical implications of long Non-Coding RNAs in melanoma. Int J Mol Sci. 18:7152017. View Article : Google Scholar : PubMed/NCBI
13	Riefolo M, Porcellini E, Dika E, Broseghini E and Ferracin M: Interplay between small and long non-coding RNAs in cutaneous melanoma: A complex jigsaw puzzle with missing pieces. Mol Oncol. 13:74–98. 2019. View Article : Google Scholar : PubMed/NCBI
14	Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, Radaelli E, Eyckerman S, Leonelli C, Vanderheyden K, et al: Melanoma addiction to the long non-coding RNA SAMMSON. Nature. 531:518–522. 2016. View Article : Google Scholar : PubMed/NCBI
15	Wu K, Wang Q, Liu YL, Xiang Z, Wang QQ, Yin L and Liu SL: LncRNA POU3F3 contributes to dacarbazine resistance of human melanoma through the MiR-650/MGMT Axis. Front Oncol. 11:6436132021. View Article : Google Scholar : PubMed/NCBI
16	Attrill GH, Ferguson PM, Palendira U, Long GV, Wilmott JS and Scolyer RA: The tumour immune landscape and its implications in cutaneous melanoma. Pigment Cell Melanoma Res. 34:529–549. 2021. View Article : Google Scholar : PubMed/NCBI
17	Wu M, Fu P, Qu L, Liu J and Lin A: Long noncoding RNAs, new critical regulators in cancer immunity. Front Oncol. 10:5509872020. View Article : Google Scholar : PubMed/NCBI
18	Zhang K, Zhang L, Mi Y, Tang Y, Ren F, Liu B, Zhang Y and Zheng P: A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration. Cancer Sci. 111:4041–4050. 2020. View Article : Google Scholar : PubMed/NCBI
19	Li G, Kryczek I, Nam J, Li X, Li S, Li J, Wei S, Grove S, Vatan L, Zhou J, et al: LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy. Nat Cell Biol. 23:526–537. 2021. View Article : Google Scholar : PubMed/NCBI
20	Appelbaum EN, Gross ND, Diab A, Bishop AJ, Nader ME and Gidley PW: Melanoma of the external auditory canal: A review of seven cases at a tertiary care referral center. Laryngoscope. 131:165–172. 2021. 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	Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES and Mesirov JP: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 102:15545–15550. 2005. View Article : Google Scholar : PubMed/NCBI
23	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hänzelmann S, Castelo R and Guinney J: GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 14:72013. View Article : Google Scholar : PubMed/NCBI
25	Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al: Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 39:782–795. 2013. View Article : Google Scholar : PubMed/NCBI
26	Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, et al: An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 173:400–416.e11. 2018. View Article : Google Scholar : PubMed/NCBI
27	Leucci E, Coe EA, Marine JC and Vance KW: The emerging role of long non-coding RNAs in cutaneous melanoma. Pigment Cell Melanoma Res. 29:619–626. 2016. View Article : Google Scholar : PubMed/NCBI
28	Ma W, Qiao J, Zhou J, Gu L and Deng D: Characterization of novel LncRNA P14AS as a protector of ANRIL through AUF1 binding in human cells. Mol Cancer. 19:422020. View Article : Google Scholar : PubMed/NCBI
29	Vishnubalaji R, Shaath H, Elkord E and Alajez NM: Long non-coding RNA (lncRNA) transcriptional landscape in breast cancer identifies LINC01614 as non-favorable prognostic biomarker regulated by TGFbeta and focal adhesion kinase (FAK) signaling. Cell Death Discov. 5:1092019. View Article : Google Scholar : PubMed/NCBI
30	Dunn GP, Koebel CM and Schreiber RD: Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 6:836–848. 2006. View Article : Google Scholar : PubMed/NCBI
31	von Locquenghien M, Rozalen C and Celia-Terrassa T: Interferons in cancer immunoediting: Sculpting metastasis and immunotherapy response. J Clin Invest. 131:e1432962021. View Article : Google Scholar : PubMed/NCBI
32	Alavi S, Stewart AJ, Kefford RF, Lim SY, Shklovskaya E and Rizos H: Interferon signaling is frequently downregulated in melanoma. Front Immunol. 9:14142018. View Article : Google Scholar : PubMed/NCBI
33	Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, et al: Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19:1189–1201. 2017. View Article : Google Scholar : PubMed/NCBI
34	Lin JX and Leonard WJ: The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 19:2566–2576. 2000. View Article : Google Scholar : PubMed/NCBI
35	Yu Y, Zhang W, Li A, Chen Y, Ou Q, He Z, Zhang Y, Liu R, Yao H and Song E: Association of long noncoding RNA biomarkers with clinical immune subtype and prediction of immunotherapy response in patients with cancer. JAMA Netw Open. 3:e2021492020. View Article : Google Scholar : PubMed/NCBI
36	Shen M, Pan X, Gao Y, Ye H, Zhang J, Chen Y, Pan M, Huang W, Xu X, Zhan Y and Jin L: LncRNA CRNDE exacerbates IgA nephropathy progression by promoting NLRP3 inflammasome activation in macrophages. Immunol Invest. 7:1–13. 2021. View Article : Google Scholar
37	Ladányi A: Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res. 28:490–500. 2015. View Article : Google Scholar : PubMed/NCBI
38	Ladányi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, Gaudi I and Tímár J: Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother. 56:1459–1469. 2007. View Article : Google Scholar : PubMed/NCBI
39	Fridman WH, Pagès F, Sautès-Fridman C and Galon J: The immune contexture in human tumours: Impact on clinical outcome. Nat Rev Cancer. 12:298–306. 2012. View Article : Google Scholar : PubMed/NCBI
40	Kobayashi T, Hamaguchi Y, Hasegawa M, Fujimoto M, Takehara K and Matsushita T: B cells promote tumor immunity against B16F10 melanoma. Am J Pathol. 184:3120–3129. 2014. View Article : Google Scholar : PubMed/NCBI
41	Garg K, Maurer M, Griss J, Brüggen MC, Wolf IH, Wagner C, Willi N, Mertz KD and Wagner SN: Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome. Hum Pathol. 54:157–164. 2016. View Article : Google Scholar : PubMed/NCBI
42	Monti M, Consoli F, Vescovi R, Bugatti M and Vermi W: Human plasmacytoid dendritic cells and cutaneous melanoma. Cells. 9:4172020. View Article : Google Scholar : PubMed/NCBI