CTHRC1 is associated with immune cell infiltration and functions as an adverse marker for prognosis in head and neck squamous cell carcinoma

Zhong,Ruolei; Yang,Mengling; Zhu,Rui; Zhang,Jiahua; Wang,Li

doi:10.3892/ol.2023.13719

CTHRC1 is associated with immune cell infiltration and functions as an adverse marker for prognosis in head and neck squamous cell carcinoma

Authors:
- Ruolei Zhong
- Mengling Yang
- Rui Zhu
- Jiahua Zhang
- Li Wang
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Affiliations: Department of Hepatobiliary Surgery, Affiliated Hospital of Jianghan University, Wuhan, Hubei 430015, P.R. China, Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: February 15, 2023 https://doi.org/10.3892/ol.2023.13719
Article Number: 133
Copyright: © Zhong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Collagen triple helix repeat containing 1 (CTHRC1) is a secreted glycoprotein that decreases the deposition of collagen matrix and accelerates tumor metastasis. However, the relationship between CTHRC1 and the outcomes of head and neck squamous cell carcinoma (HNSCC) and tumor‑infiltrating lymphocytes remains unclear. In the present study, the transcriptional level of CTHRC1 and its association with overall survival (OS) and relapse‑free survival (RFS) time in diverse cancer types were evaluated using The Cancer Genome Atlas, Tumor Immune Estimation Resource (TIMER), ONCOMINE and Kaplan‑Meier plotter databases. The association of CTHRC1 expression level with the clinicopathological parameters of patients with HNSCC from The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) database were also evaluated. Enrichment analysis of CTHRC1 was carried out using gene set enrichment analysis software. CIBERSORT and TIMER databases were used to evaluate the relationship between the expression level of CTHRC1 and the proportion of tumor‑infiltrating immune cells (TICs) in multiple cancer types. Moreover, immunohistochemistry was used to verify the expression of CTHRC1 in clinical samples of HNSCC. CTHRC1 was upregulated in HNSCC and high expression of CTHRC1 was associated with worsening clinicopathologic parameters and shorter OS and RFS times. There were eight HALLMARK gene sets, 1,231 immune signature gene sets and 14 KEGG gene sets significantly enriched in the high CTHRC1 expression group, while no gene set was enriched in the low CTHRC1 expression group. The expression of CTHRC1 was closely correlated with the proportion of TICs, where the expression of CTHRC1 was significantly positively correlated with the amount of infiltrated M0 and M2 macrophages, and significantly negatively associated with the levels of M1 macrophages. These findings suggest that CTHRC1 is an adverse prognostic marker and is associated with immune cell infiltration in HNSCC.

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1	Wyss A, Hashibe M, Chuang SC, Lee YC, Zhang ZF, Yu GP, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N, et al: Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: Pooled analysis in the international head and neck cancer epidemiology consortium. Am J Epidemiol. 178:679–690. 2013. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Ferris RL: Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 33:3293–3304. 2015. View Article : Google Scholar : PubMed/NCBI
4	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
5	Kuss I, Hathaway B, Ferris RL, Gooding W and Whiteside TL: Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res. 10:3755–3762. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bauernhofer T, Kuss I, Henderson B, Baum AS and Whiteside TL: Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. 33:119–124. 2003. View Article : Google Scholar : PubMed/NCBI
7	Ferris RL: Progress in head and neck cancer immunotherapy: Can tolerance and immune suppression be reversed? ORL J Otorhinolaryngol Relat Spec. 66:332–340. 2004. View Article : Google Scholar : PubMed/NCBI
8	Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet. 394:1915–1928. 2019. View Article : Google Scholar : PubMed/NCBI
9	Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al: Nivolumab for recurrent squamous-cell carcinoma of the head and neck. New Engl J Med. 375:1856–1867. 2016. View Article : Google Scholar : PubMed/NCBI
10	Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L, Friesel RE and Lindner V: Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration. Circ Res. 96:261–268. 2005. View Article : Google Scholar : PubMed/NCBI
11	Duan X, Yuan X, Yao B, Song W, Li Z, Enhejirigala, Kong Y, Wang Y, Fu X and Huang S: The role of CTHRC1 in promotion of cutaneous wound healing. Signal Transduct Target Ther. 7:1832022. View Article : Google Scholar : PubMed/NCBI
12	Bian Z, Miao Q, Zhong W, Zhang H, Wang Q, Peng Y, Chen X, Guo C, Shen L, Yang F, et al: Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease. J Autoimmun. 63:76–87. 2015. View Article : Google Scholar : PubMed/NCBI
13	Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, Ito M and Ikeda K: Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest. 123:3914–3924. 2013. View Article : Google Scholar : PubMed/NCBI
14	Stohn JP, Wang Q, Siviski ME, Kennedy K, Jin YR, Kacer D, DeMambro V, Liaw L, Vary CP, Rosen CJ, et al: Cthrc1 controls adipose tissue formation, body composition, and physical activity. Obesity (Silver Spring). 23:1633–1642. 2015. View Article : Google Scholar : PubMed/NCBI
15	Ni SJ, Ren F, Xu M, Tan C, Weng W, Huang Z, Sheng W and Huang D: CTHRC1 overexpression predicts poor survival and enhances epithelial-mesenchymal transition in colorectal cancer. Cancer Med. 7:5643–5654. 2018. View Article : Google Scholar : PubMed/NCBI
16	Ding X, Huang R, Zhong Y, Cui N, Wang Y, Weng J, Chen L and Zang M: CTHRC1 promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway. Biomed Pharmacother. 123:1097422020. View Article : Google Scholar : PubMed/NCBI
17	Yan L, Yu J, Tan F, Ye GT, Shen ZY, Liu H, Zhang Y, Wang JF, Zhu XJ and Li GX: SP1-mediated microRNA-520d-5p suppresses tumor growth and metastasis in colorectal cancer by targeting CTHRC1. Am J Cancer Res. 5:1447–1459. 2015.PubMed/NCBI
18	Ma MZ, Zhuang C, Yang XM, Zhang ZZ, Ma H, Zhang WM, You H, Qin W, Gu J, Yang S, et al: CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling. Neoplasia. 16:265–278. 278e1–e13. 2014. View Article : Google Scholar : PubMed/NCBI
19	Hou MZ, Cheng ZQ, Shen HW, He S, Li Y, Pan Y, Feng C, Chen X, Zhang Y, Lin M, et al: High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis. Oncotarget. 6:35813–35829. 2015. View Article : Google Scholar : PubMed/NCBI
20	Wang C, Li Z, Shao F, Yang X, Feng X, Shi S, Gao Y and He J: High expression of collagen triple helix repeat containing 1 (CTHRC1) facilitates progression of oesophageal squamous cell carcinoma through MAPK/MEK/ERK/FRA-1 activation. J Exp Clin Canc Res. 36:842017. View Article : Google Scholar : PubMed/NCBI
21	Zheng M, Zhou Q, Liu X, Wang C and Liu G: CTHRC1 overexpression promotes cervical carcinoma progression by activating the Wnt/PCP signaling pathway. Oncol Rep. 41:1531–1538. 2019.PubMed/NCBI
22	Yuan RX, Bao D and Zhang Y: Linc00707 promotes cell proliferation, invasion, and migration via the miR-30c/CTHRC1 regulatory loop in breast cancer. Eur Rev Med Pharmaco. 24:4863–4872. 2020.PubMed/NCBI
23	Zhou H, Su L, Liu C, Li B, Li H, Xie Y and Sun D: CTHRC1 may serve as a prognostic biomarker for hepatocellular carcinoma. Onco Targets Ther. 12:7823–7831. 2019. View Article : Google Scholar : PubMed/NCBI
24	Sial N, Ahmad M, Hussain MS, Iqbal MJ, Hameed Y, Khan M, Abbas M, Asif R, Rehman JU, Atif M, et al: CTHRC1 expression is a novel shared diagnostic and prognostic biomarker of survival in six different human cancer subtypes. Sci Rep. 11:198732021. View Article : Google Scholar : PubMed/NCBI
25	Bai Y, Yin K, Su T, Ji F and Zhang S: CTHRC1 in ovarian cancer promotes M2-like polarization of tumor-associated macrophages via regulation of the STAT6 signaling pathway. Onco Targets Ther. 13:5743–5753. 2020. View Article : Google Scholar : PubMed/NCBI
26	Wang Z, Jensen MA and Zenklusen JC: A practical guide to the cancer genome atlas (TCGA). Methods Mol Biol. 1418:111–141. 2016. View Article : Google Scholar : PubMed/NCBI
27	Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, et al: Oncomine 3.0: Genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 9:166–180. 2007. View Article : Google Scholar : PubMed/NCBI
28	Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B and Liu XS: TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77:e108–e110. 2017. View Article : Google Scholar : PubMed/NCBI
29	Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK and Varambally S: UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 19:649–658. 2017. View Article : Google Scholar : PubMed/NCBI
30	Reis-Filho JS and Tutt ANJ: Triple negative tumours: A critical review. Histopathology. 52:108–118. 2008. View Article : Google Scholar : PubMed/NCBI
31	Shien T, Shimizu C, Seki K, Shibata T, Hojo T, Ando M, Kohno T, Katsumata N, Akashi-Tanaka S, Kinoshita T and Fujiwara Y: Comparison among different classification systems regarding the pathological response of preoperative chemotherapy in relation to the long-term outcome. Breast Cancer Res Treat. 113:307–313. 2008. View Article : Google Scholar : PubMed/NCBI
32	Lánczky A and Győrffy B: Web-based survival analysis tool tailored for medical research (KMplot): Development and implementation. J Med Internet Res. 23:e276332021. View Article : Google Scholar : PubMed/NCBI
33	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022. View Article : Google Scholar : PubMed/NCBI
34	Lee CE, Vincent-Chong VK, Ramanathan A, Kallarakkal TG, Karen-Ng LP, Ghani WM, Rahman ZA, Ismail SM, Abraham MT, Tay KK, et al: Collagen triple helix repeat containing-1 (CTHRC1) expression in oral squamous cell carcinoma (OSCC): Prognostic value and clinico-pathological implications. Int J Med Sci. 12:937–945. 2015. View Article : Google Scholar : PubMed/NCBI
35	Liu GL, Sengupta PK, Jamal B, Yang HY, Bouchie MP, Lindner V, Varelas X and Kukuruzinska MA: N-glycosylation induces the CTHRC1 protein and drives oral cancer cell migration. J Biol Chem. 288:20217–20227. 2013. View Article : Google Scholar : PubMed/NCBI
36	Scheel C, Eaton EN, Li SHJ, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL and Weinberg RA: Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 145:926–940. 2011. View Article : Google Scholar : PubMed/NCBI
37	Weidhaas JB, Harris J, Schaue D, Chen AM, Chin R, Axelrod R, El-Naggar AK, Singh AK, Galloway TJ, Raben D, et al: The KRAS-variant and cetuximab response in head and neck squamous cell cancer: A secondary analysis of a randomized clinical trial. JAMA Oncol. 3:483–491. 2017. View Article : Google Scholar : PubMed/NCBI
38	Loganathan SK, Schleicher K, Malik A, Quevedo R, Langille E, Teng K, Oh RH, Rathod B, Tsai R, Samavarchi-Tehrani P, et al: Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling. Science. 367:1264–1269. 2020. View Article : Google Scholar : PubMed/NCBI
39	Oshimori N, Oristian D and Fuchs E: TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 160:963–976. 2015. View Article : Google Scholar : PubMed/NCBI
40	Guo B, Yan H, Li L, Yin K, Ji F and Zhang S: Collagen triple helix repeat containing 1 (CTHRC1) activates Integrin β3/FAK signaling and promotes metastasis in ovarian cancer. J Ovarian Res. 10:692017. View Article : Google Scholar : PubMed/NCBI