CLEC3B is downregulated and inhibits proliferation in clear cell renal cell carcinoma

Liu,Jian; Liu,Zhe; Liu,Qun; Li,Lina; Fan,Xiaona; Wen,Tao; An,Guangyu

doi:10.3892/or.2018.6590

CLEC3B is downregulated and inhibits proliferation in clear cell renal cell carcinoma

Authors:
- Jian Liu
- Zhe Liu
- Qun Liu
- Lina Li
- Xiaona Fan
- Tao Wen
- Guangyu An
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Affiliations: Medical Research Center, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Oncology, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Obstetrics and Gynecology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
Published online on: July 23, 2018 https://doi.org/10.3892/or.2018.6590
Pages: 2023-2035
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Dysregulation of C‑Type Lectin Domain Family 3 Member B (CLEC3B) in serum or tumor tissues has been reported in patients with various cancer types. However, the expression and function of CLEC3B in clear cell renal cell carcinoma (ccRCC) remain unknown. To examine the function of CLEC3B in ccRCC, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were examined to determine the expression of CLEC3B at the transcriptional level and it was demonstrated that CLEC3B mRNA was significantly downregulated in ccRCC compared with normal tissues (P<0.0001 and P=0.0392 in TCGA and GEO databases, respectively). The downregulation of CLEC3B was further validated at the protein level in 78.9% of ccRCCs by immunohistochemistry. To investigate the potential genetic mechanism for CLEC3B downregulation in ccRCC, copy number analysis was performed by profiling the copy number variation data from the TCGA project and it was revealed that the copy number loss of CLEC3B was prevalent in up to 88.1% of patients with ccRCC. CLEC3B genetic deletion was coupled with the well‑known genetic loss of the von Hippel‑Lindau tumor suppressor, which is a characteristic oncogenic event during ccRCC carcinogenesis. The downregulation of CLEC3B was associated with tumor progression and predicted unfavorable prognostic outcomes in the TCGA cohort. Real‑time cell analyzer system technology revealed that CLEC3B inhibited the proliferation of ccRCC cell lines in vitro and that the mitogen‑activated protein kinase pathway may contribute to this process. CLEC3B demonstrated substantial positive associations with proliferation inhibitors, but inverse associations with proliferation inducers and markers in two large ccRCC cohorts, suggesting that CLEC3B was able to identify ccRCCs with a lower proliferation capacity. In conclusion, the results of the present study propose that CLEC3B is a promising target for therapeutic intervention in ccRCC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Rini BI, Campbell SC and Escudier B: Renal cell carcinoma. Lancet. 373:1119–1132. 2009. View Article : Google Scholar : PubMed/NCBI
3	Wolff I, May M, Hoschke B, Zigeuner R, Cindolo L, Hutterer G, Schips L, De Cobelli O, Rocco B, De Nunzio C, et al: Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database. Eur J Surg Oncol. 42:744–750. 2016. View Article : Google Scholar : PubMed/NCBI
4	Chen F, Zhang Y, Şenbabaoğlu Y, Ciriello G, Yang L, Reznik E, Shuch B, Micevic G, De Velasco G, Shinbrot E, et al: Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 14:2476–2489. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kaelin WG Jr: The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 10:6290S–5S. 2004. View Article : Google Scholar : PubMed/NCBI
6	Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, Heng DY, Larkin J and Ficarra V: Renal cell carcinoma. Nat Rev Dis Primers. 3:170092017. View Article : Google Scholar : PubMed/NCBI
7	Iliopoulos O, Kibel A, Gray S and Kaelin WG Jr: Tumour suppression by the human von Hippel-Lindau gene product. Nat Med. 1:822–826. 1995. View Article : Google Scholar : PubMed/NCBI
8	Tanisawa K, Arai Y, Hirose N, Shimokata H, Yamada Y, Kawai H, Kojima M, Obuchi S, Hirano H, Yoshida H, et al: Exome-wide association study identifies CLEC3B missense variant p.S106G as being associated with extreme longevity in east asian populations. J Gerontol A Biol Sci Med Sci. 72:309–318. 2017.PubMed/NCBI
9	Clemmensen I, Petersen LC and Kluft C: Purification and characterization of a novel, oligomeric, plasminogen kringle 4 binding protein from human plasma: Tetranectin. Eur J Biochem. 156:327–333. 1986. View Article : Google Scholar : PubMed/NCBI
10	Wewer UM, Ibaraki K, Schjørring P, Durkin ME, Young MF and Albrechtsen R: A potential role for tetranectin in mineralization during osteogenesis. J Cell Biol. 127:1767–1775. 1994. View Article : Google Scholar : PubMed/NCBI
11	Wewer UM, Iba K, Durkin ME, Nielsen FC, Loechel F, Gilpin BJ, Kuang W, Engvall E and Albrechtsen R: Tetranectin is a novel marker for myogenesis during embryonic development, muscle regeneration, and muscle cell differentiation in vitro. Dev Biol. 200:247–259. 1998. View Article : Google Scholar : PubMed/NCBI
12	Yin X, Subramanian S, Hwang SJ, O'Donnell CJ, Fox CS, Courchesne P, Muntendam P, Gordon N, Adourian A, Juhasz P, et al: Protein biomarkers of new-onset cardiovascular disease: Prospective study from the systems approach to biomarker research in cardiovascular disease initiative. Arterioscler Thromb Vasc Biol. 34:939–945. 2014. View Article : Google Scholar : PubMed/NCBI
13	Chen Y, Han H, Yan X, Ding F, Su X, Wang H, Chen Q, Lu L, Zhang R and Jin W: Tetranectin as a potential biomarker for stable coronary artery disease. Sci Rep. 5:176322015. View Article : Google Scholar : PubMed/NCBI
14	Chen Z, Wang E, Hu R, Sun Y, Zhang L, Jiang J, Zhang Y and Jiang H: Tetranectin gene deletion induces Parkinson's disease by enhancing neuronal apoptosis. Biochem Biophys Res Commun. 468:400–407. 2015. View Article : Google Scholar : PubMed/NCBI
15	Jensen BA and Clemmensen I: Plasma tetranectin is reduced in cancer and related to metastasia. Cancer. 62:869–872. 1988. View Article : Google Scholar : PubMed/NCBI
16	Nielsen H, Clemmensen I, Nielsen HJ and Drivsholm A: Decreased tetranectin in multiple myeloma. Am J Hematol. 33:142–144. 1990. View Article : Google Scholar : PubMed/NCBI
17	Høgdall CK, Høgdall EV, Hørding U, Daugaard S, Clemmensen I, Nørgaard-Pedersen B and Toftager-Larsen K: Plasma tetranectin and ovarian neoplasms. Gynecol Oncol. 43:103–107. 1991. View Article : Google Scholar : PubMed/NCBI
18	Høgdall CK, Christiansen M, Nørgaard-Pedersen B, Bentzen SM, Kronborg O and Clemmensen I: Plasma tetranectin and colorectal cancer. Eur J Cancer. 31A:888–894. 1995. View Article : Google Scholar : PubMed/NCBI
19	Felix K, Hauck O, Fritz S, Hinz U, Schnölzer M, Kempf T, Warnken U, Michel A, Pawlita M and Werner J: Serum protein signatures differentiating autoimmune pancreatitis versus pancreatic cancer. PLoS One. 8:e827552013. View Article : Google Scholar : PubMed/NCBI
20	Lundstrøm MS, Høgdall CK, Nielsen AL and Nyholm HC: Serum tetranectin and CA125 in endometrial adenocarcinoma. Anticancer Res. 20:3903–3906. 2000.PubMed/NCBI
21	Arellano-Garcia ME, Li R, Liu X, Xie Y, Yan X, Loo JA and Hu S: Identification of tetranectin as a potential biomarker for metastatic oral cancer. Int J Mol Sci. 11:3106–3121. 2010. View Article : Google Scholar : PubMed/NCBI
22	Høgdall CK, Hørding U, Nørgaard-Pedersen B, Toftager-Larsen K and Clemmensen I: Serum tetranectin and CA-125 used to monitor the course of treatment in ovarian cancer patients. Eur J Obstet Gynecol Reprod Biol. 57:175–178. 1994. View Article : Google Scholar : PubMed/NCBI
23	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. 8:3623–3630. 2017. View Article : Google Scholar : PubMed/NCBI
24	Obrist P, Spizzo G, Ensinger C, Fong D, Brunhuber T, Schäfer G, Varga M, Margreiter R, Amberger A, Gastl G and Christiansen M: Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol. 57:417–421. 2004. View Article : Google Scholar : PubMed/NCBI
25	Heeran MC, Rask L, Høgdall CK, Kjaer SK, Christensen L, Jensen A, Blaakaer J, Christensen Jarle IB and Høgdall EV: Tetranectin positive expression in tumour tissue leads to longer survival in Danish women with ovarian cancer. Results from the ‘Malova’ ovarian cancer study. APMIS. 123:401–409. 2015. View Article : Google Scholar : PubMed/NCBI
26	Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R and Getz G: GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12:R412011. View Article : Google Scholar : PubMed/NCBI
27	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
28	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
29	Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, et al: Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 509:91–95. 2014. View Article : Google Scholar : PubMed/NCBI
30	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
31	Huang dW, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
32	Lam JS, Klatte T and Breda A: Staging of renal cell carcinoma: Current concepts. Indian J Urol. 25:446–454. 2009. View Article : Google Scholar : PubMed/NCBI
33	Moch H: The WHO/ISUP grading system for renal carcinoma. Pathologe. 37:355–360. 2016.(In German). View Article : Google Scholar : PubMed/NCBI
34	Beroukhim R, Brunet JP, Di Napoli A, Mertz KD, Seeley A, Pires MM, Linhart D, Worrell RA, Moch H, Rubin MA, et al: Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69:4674–4681. 2009. View Article : Google Scholar : PubMed/NCBI
35	Macé A, Kutalik Z and Valsesia A: Copy number variation. Methods Mol Biol. 1793:231–258. 2018. View Article : Google Scholar : PubMed/NCBI
36	Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, et al: Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 14:4726–4734. 2008. View Article : Google Scholar : PubMed/NCBI
37	Zhang W and Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12:9–18. 2002. View Article : Google Scholar : PubMed/NCBI
38	van Dam S, Võsa U, van der Graaf A, Franke L and de Magalhães J: Gene co-expression analysis for functional classification and gene-disease predictions. Brief Bioinform. 2017. View Article : Google Scholar :
39	Cecchi F, Rabe DC and Bottaro DP: Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 46:1260–1270. 2010. View Article : Google Scholar : PubMed/NCBI
40	Justilien V, Ali SA, Jamieson L, Yin N, Cox AD, Der CJ, Murray NR and Fields AP: Ect2-dependent rRNA synthesis is required for KRAS-TRP53-driven lung adenocarcinoma. Cancer Cell. 31:256–269. 2017. View Article : Google Scholar : PubMed/NCBI
41	Bracken AP, Pasini D, Capra M, Prosperini E, Colli E and Helin K: EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22:5323–5335. 2003. View Article : Google Scholar : PubMed/NCBI
42	Ryu S and Driever W: Minichromosome maintenance proteins as markers for proliferation zones during embryogenesis. Cell Cycle. 5:1140–1142. 2006. View Article : Google Scholar : PubMed/NCBI
43	Guo Y, Xie J, Rubin E, Tang YX, Lin F, Zi X and Hoang BH: Frzb, a secreted Wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of Met signaling. Cancer Res. 68:3350–3360. 2008. View Article : Google Scholar : PubMed/NCBI
44	Andreeva AV and Kutuzov MA: Cadherin 13 in cancer. Genes Chromosomes Cancer. 49:775–790. 2010.PubMed/NCBI
45	Liu X, Lan Y, Zhang D, Wang K, Wang Y and Hua ZC: SPRY1 promotes the degradation of uPAR and inhibits uPAR-mediated cell adhesion and proliferation. Am J Cancer Res. 4:683–697. 2014.PubMed/NCBI
46	Oh KY, Hong KO, Huh YS, Lee JI and Hong SD: Decreased expression of SOX7 induces cell proliferation and invasion and correlates with poor prognosis in oral squamous cell carcinoma. J Oral Pathol Med. 46:752–758. 2017. View Article : Google Scholar : PubMed/NCBI
47	Jafri M, Wake NC, Ascher DB, Pires DE, Gentle D, Morris MR, Rattenberry E, Simpson MA, Trembath RC, Weber A, et al: Germline Mutations in the CDKN2B tumor suppressor gene predispose to renal cell carcinoma. Cancer Discov. 5:723–729. 2015. View Article : Google Scholar : PubMed/NCBI
48	Paz N, Levanon EY, Amariglio N, Heimberger AB, Ram Z, Constantini S, Barbash ZS, Adamsky K, Safran M, Hirschberg A, et al: Altered adenosine-to-inosine RNA editing in human cancer. Genome Res. 17:1586–1595. 2007. View Article : Google Scholar : PubMed/NCBI
49	Sánchez-Martín D, Otsuka A, Kabashima K, Ha T, Wang D, Qian X, Lowy DR and Tosato G: Effects of DLC1 deficiency on endothelial cell contact growth inhibition and angiosarcoma progression. J Natl Cancer Inst. 110:390–399. 2017. View Article : Google Scholar :
50	Kim YM, Stone M, Hwang TH, Kim YG, Dunlevy JR, Griffin TJ and Kim DH: SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling. Mol Cell. 46:833–846. 2012. View Article : Google Scholar : PubMed/NCBI
51	Shen YJ, Kong ZL, Wan FN, Wang HK, Bian XJ, Gan HL, Wang CF and Ye DW: Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer. Cancer Sci. 105:704–712. 2014. View Article : Google Scholar : PubMed/NCBI
52	Høgdall CK, Christensen L and Clemmensen I: The prognostic value of tetranectin immunoreactivity and plasma tetranectin in patients with ovarian cancer. Cancer. 72:2415–2422. 1993. View Article : Google Scholar : PubMed/NCBI
53	Høgdall CK, Sölétormos G, Nielsen D, Nørgaard-Pedersen B, Dombernowsky P and Clemmensen I: Prognostic value of serum tetranectin in patients with metastatic breast cancer. Acta Oncol. 32:631–636. 1993. View Article : Google Scholar : PubMed/NCBI
54	Bamborough P, Chung CW, Demont EH, Furze RC, Bannister AJ, Che KH, Diallo H, Douault C, Grandi P, Kouzarides T, et al: A Chemical probe for the ATAD2 bromodomain. Angew Chem Int Ed Engl. 55:11382–11386. 2016. View Article : Google Scholar : PubMed/NCBI
55	Saha A, Kim Y, Gewirtz ADH, Jo B, Gao C and McDowell IC: GTEx Consortium, Engelhardt BE and Battle A: Co-expression networks reveal the tissue-specific regulation of transcription and splicing. Genome Res. 27:1843–1858. 2017. View Article : Google Scholar : PubMed/NCBI