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Cancer Cell International
Published in: Cancer Cell International 1/2020

01-12-2020 | Lung Cancer | Primary research

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

Authors: Jiaxing Sun, Tian Xie, Muhammad Jamal, Zhenbo Tu, Xinran Li, Yingjie Wu, Jingyuan Li, Qiuping Zhang, Xiaoxing Huang

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Lung cancer is the leading cause of cancer-related mortality globally. Discovering effective biomarkers for early diagnosis and prognosis is important to reduce the mortality rate and ensure efficient therapy for lung cancer patients. C-type lectin domain family 3 member B (CLEC3B) has been reported in various cancers, but its correlation with lung cancer remains elusive.

Methods

The GEO, TCGA and Oncomine databases were analyzed to examine the expression of CLEC3B in lung cancer. The CLEC3B mRNA levels in 15 patient tissue samples were detected by real-time PCR and the CLEC3B protein levels in 34 patient tissue samples were detected by immunohistochemistry. A Chi-square test was performed to analyze the correlation of CLEC3B expression and clinicopathological factors. The diagnostic value of CLEC3B was revealed by receiver operating characteristic (ROC) curves. Univariate and multivariate Cox proportional hazards regression models and Kaplan–Meier plots were used to evaluate the prognostic value of CLEC3B in lung cancer. The TIMER database was used to evaluate the correlation of CLEC3B and immune infiltration. Gene set enrichment analysis revealed tumor‐associated biological processes related to CLEC3B.

Results

CLEC3B is significantly downregulated in lung cancer patients compared with nontumor controls according to database analysis and patient tissue sample detection (p < 0.001). Specifically, CLEC3B is significantly downregulated in stage IA lung cancer patients (p < 0.001) and has a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). Moreover, low expression of CLEC3B is related to poor progression-free survival (HR = 0.60, 95% CI 0.49–0.74, p = 8.3e−07) and overall survival (HR = 0.66, 95% CI 0.58–0.75, p = 2.1e−10), indicating it as a risk factor for lung cancer. Multivariate analysis value showed that low expression of CLEC3B may be an independent risk factor for disease‐free survival in lung cancer patients (HR = 0.655, 95% CI 0.430–0.996, Cox p = 0.048). In addition, we also investigated the potential role of CLEC3B in tumor-immune interactions and found that CLEC3B might be associated with the immune infiltration and immune activation of lung cancer, especially in squamous cell carcinoma.

Conclusions

Our findings indicate that CLEC3B expression is downregulated in lung cancer and reveal the diagnostic and prognostic potential of CLEC3B in lung cancer and its potential as an immune-related therapeutic target in lung cancer.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMed
2.
Heuvers ME, Wisnivesky J, Stricker BH, Aerts JG. Generalizability of results from the National Lung Screening Trial. Eur J Epidemiol. 2012;27(9):669–72.PubMedCrossRef
3.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.PubMedCrossRef
4.
Lim E, Tay A, Von Der Thusen J, Freidin MB, Anikin V, Nicholson AG. Clinical results of microfluidic antibody-independent peripheral blood circulating tumor cell capture for the diagnosis of lung cancer. J Thorac Cardiovasc Surg. 2014;147(6):1936–8.PubMedCrossRef
5.
Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, Paz-Ares L. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389(10066):299–311.PubMedCrossRef
6.
Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, Ni A, Novik JB, Mangarin LMB, Abu-Akeel M, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(5):843–52.PubMedPubMedCentralCrossRef
7.
Varn FS, Tafe LJ, Amos CI, Cheng C. Computational immune profiling in lung adenocarcinoma reveals reproducible prognostic associations with implications for immunotherapy. Oncoimmunology. 2018;7(6):e1431084.PubMedPubMedCentralCrossRef
8.
Dai W, Wang Y, Yang T, Wang J, Wu W, Gu J. Downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMPK and VEGF signals. Cell Commun Signal. 2019;17(1):113.PubMedPubMedCentralCrossRef
9.
Zhu HF, Zhang XH, Gu CS, Zhong Y, Long T, Ma YD, Hu ZY, Li ZG, Wang XY. Cancer-associated fibroblasts promote colorectal cancer progression by secreting CLEC3B. Cancer Biol Ther. 2019;20(7):967–78.PubMedPubMedCentralCrossRef
10.
Clemmensen I, Petersen LC, Kluft C. Purification and characterization of a novel, oligomeric, plasminogen kringle 4 binding protein from human plasma: tetranectin. Eur J Biochem. 1986;156(2):327–33.PubMedCrossRef
11.
Obrist P, Spizzo G, Ensinger C, Fong D, Brunhuber T, Schafer G, Varga M, Margreiter R, Amberger A, Gastl G, et al. Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol. 2004;57(4):417–21.PubMedPubMedCentralCrossRef
12.
Dano K, Behrendt N, Hoyer-Hansen G, Johnsen M, Lund LR, Ploug M, Romer J. Plasminogen activation and cancer. Thromb Haemostat. 2005;93(4):676–81.CrossRef
13.
De Vries TJ, De Wit PE, Clemmensen I, Verspaget HW, Weidle UH, Brocker EB, Ruiter DJ, Van Muijen GN. Tetranectin and plasmin/plasminogen are similarly distributed at the invasive front of cutaneous melanoma lesions. J Pathol. 1996;179(3):260–5.PubMedCrossRef
14.
Qadir F, Lalli A, Dar HH, Hwang S, Aldehlawi H, Ma H, Dai H, Waseem A, Teh MT. Clinical correlation of opposing molecular signatures in head and neck squamous cell carcinoma. BMC Cancer. 2019;19(1):830.PubMedPubMedCentralCrossRef
15.
Liu J, Liu Z, Liu Q, Li L, Fan X, Wen T, An G. CLEC3B is downregulated and inhibits proliferation in clear cell renal cell carcinoma. Oncol Rep. 2018;40(4):2023–35.PubMedPubMedCentral
16.
Chen H, Li H, Zhao J, Peng P, Shao M, Wu H, Wang X, Chen L, Zhang Q, Ruan Y, et al. High intratumoral expression of tetranectin associates with poor prognosis of patients with gastric cancer after gastrectomy. J Cancer. 2017;8(17):3623–30.PubMedPubMedCentralCrossRef
17.
Galamb O, Kalmar A, Bartak BK, Patai AV, Leiszter K, Peterfia B, Wichmann B, Valcz G, Veres G, Tulassay Z, et al. Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma. World J Gastroenterol. 2016;22(47):10325–40.PubMedPubMedCentralCrossRef
18.
Arellano-Garcia ME, Li R, Liu X, Xie Y, Yan X, Loo JA, Hu S. Identification of tetranectin as a potential biomarker for metastatic oral cancer. Int J Mol Sci. 2010;11(9):3106–21.PubMedPubMedCentralCrossRef
19.
Deng X, Hogdall EV, Hogdall CK, Norgaard-Pedersen B, Jorgensen M, Nielsen H, Engelholm SA. The prognostic value of pretherapeutic tetranectin and CA-125 in patients with relapse of ovarian cancer. Gynecol Oncol. 2000;79(3):416–9.PubMedCrossRef
20.
Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Trevino V, Shen H, Laird PW, Levine DA, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.PubMedCrossRef
21.
Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77(21):e108–10.PubMedPubMedCentralCrossRef
22.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. P Natl Acad Sci USA. 2005;102(43):15545–50.CrossRef
23.
Nagy A, Lanczky A, Menyhart O, Gyorffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep. 2018;8:9227.PubMedPubMedCentralCrossRef
24.
Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17(1):174.PubMedPubMedCentralCrossRef
25.
Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13.PubMedCrossRef
26.
Lohr M, Edlund K, Botling J, Hammad S, Hellwig B, Othman A, Berglund A, Lambe M, Holmberg L, Ekman S, et al. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 2013;333(2):222–8.PubMedCrossRef
27.
Marshall EA, Ng KW, Kung SH, Conway EM, Martinez VD, Halvorsen EC, Rowbotham DA, Vucic EA, Plumb AW, Becker-Santos DD, et al. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. Mol Cancer. 2016;15(1):67.PubMedPubMedCentralCrossRef
28.
Stankovic B, Bjorhovde HAK, Skarshaug R, Aamodt H, Frafjord A, Muller E, Hammarstrom C, Beraki K, Baekkevold ES, Woldbaek PR, et al. Immune cell composition in human non-small cell lung cancer. Front Immunol. 2018;9:3101.PubMedCrossRef
29.
Wang SS, Liu W, Ly D, Xu H, Qu L, Zhang L. Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. Cell Mol Immunol. 2019;16(1):6–18.PubMedCrossRef
30.
31.
32.
33.
34.
Camidge DR, Doebele RC, Kerr KM. Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC. Nat Rev Clin Oncol. 2019;16(6):341–55.PubMedCrossRef
35.
Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non-small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thorac Oncol. 2015;10(7):974–84.PubMedPubMedCentralCrossRef
36.
Altorki NK, Markowitz GJ, Gao D, Port JL, Saxena A, Stiles B, McGraw T, Mittal V. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer. 2019;19(1):9–31.PubMedPubMedCentralCrossRef
37.
Muppa P, Parrilha Terra SBS, Sharma A, Mansfield AS, Aubry MC, Bhinge K, Asiedu MK, de Andrade M, Janaki N, Murphy SJ, et al. Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer. J Thorac Oncol. 2019;14(7):1286–95.PubMedCrossRef
38.
Zhang J, Wang J, Qian Z, Han Y. CCR5 is associated with immune cell infiltration and prognosis of lung cancer. J Thorac Oncol. 2019;14(5):e102–3.PubMedCrossRef
39.
Wang JB, Huang X, Li FR. Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives. Cancer Commun. 2019;39(1):43.CrossRef
40.
Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019.
41.
Zhang J, Endres S, Kobold S. Enhancing tumor T cell infiltration to enable cancer immunotherapy. Immunotherapy. 2019;11(3):201–13.PubMedCrossRef
42.
Edlund K, Madjar K, Mattsson JSM, Djureinovic D, Lindskog C, Brunnstrom H, Koyi H, Branden E, Jirstrom K, Ponten F, et al. Prognostic impact of tumor cell programmed death ligand 1 expression and immune cell infiltration in NSCLC. J Thorac Oncol. 2019;14(4):628–40.PubMedCrossRef
43.
Mei J, Xiao Z, Guo C, Pu Q, Ma L, Liu C, Lin F, Liao H, You Z, Liu L. Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: a systemic review and meta-analysis. Oncotarget. 2016;7(23):34217–28.PubMedPubMedCentralCrossRef
44.
45.
Rakaee M, Busund LR, Jamaly S, Paulsen EE, Richardsen E, Andersen S, Al-Saad S, Bremnes RM, Donnem T, Kilvaer TK. Prognostic value of macrophage phenotypes in resectable non-small cell lung cancer assessed by multiplex immunohistochemistry. Neoplasia. 2019;21(3):282–93.PubMedPubMedCentralCrossRef
46.
Meng X, Gao Y, Yang L, Jing H, Teng F, Huang Z, Xing L. Immune microenvironment differences between squamous and non-squamous non-small-cell lung cancer and their influence on the prognosis. Clin Lung Cancer. 2019;20(1):48–58.PubMedCrossRef
47.
Sun X, Xin Y, Wang M, Li S, Miao S, Xuan Y, Wang Y, Lu T, Liu J, Jiao W. Overexpression of long non-coding RNA KCNQ1OT1 is related to good prognosis via inhibiting cell proliferation in non-small cell lung cancer. Thorac Cancer. 2018;9(5):523–31.PubMedPubMedCentralCrossRef
Metadata
Title
CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment
Authors
Jiaxing Sun
Tian Xie
Muhammad Jamal
Zhenbo Tu
Xinran Li
Yingjie Wu
Jingyuan Li
Qiuping Zhang
Xiaoxing Huang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01183-1

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