Skip to main content
Top
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Primary Research

C1QTNF6 promotes oral squamous cell carcinoma by enhancing proliferation and inhibiting apoptosis

Authors: Xiaobin Song, Longjie Li, Liang Shi, Xinyu Liu, Xun Qu, Fengcai Wei, Ketao Wang

Published in: Cancer Cell International | Issue 1/2021

Login to get access

Abstract

Background

C1QTNF6 (CTRP6), a member of the CTRP family, has recently been implied to play a role in the tumorigenesis of for a variety of cancer types. However, the role of C1QTNF6 in oral squamous cell carcinoma (OSCC) and its potential molecular remains unclear.

Methods

C1QTNF6 expression was detected by qRT-PCR and western blot analysis. Lentiviral vectors were constructed to knockdown C1QTNF6 in CaL27 and SCC-9 human OSCC cell lines. Cell viability, cell cycle and cell apoptosis analyses were performed by MTT assay, PI/Annexin V staining, and flow cytometry. The effect of C1QTNF6 knockdown on in vivo tumorigenicity of OSCC cells in vivo was evaluated using nude mouse xenograft tumor model. Downstream signaling mechanisms were identified by microarray and Ingenuity Pathway Analysis.

Results

Immunohistochemistry of OSCC tissue and data from TCGA demonstrate that C1QTNF6 was overexpressed in OSCC tissues, and that cellular proliferation was significantly decreased after C1QTNF6 was knockdown in CaL27 and SCC-9 cell lines. Knockdown of C1QTNF6 also resulted in cell cycle arrest at the G2/M phase and enhanced cell apoptosis in in CaL27 and SCC-9 cell lines. Furthermore, knockdown of C1QTNF6 in Cal-27 cells inhibited tumor growth of OSCC in vivo. Microarray analysis revealed that C1QTNF6 silencing resulted in significant alterations of gene expression, with the Acute Phase Response signaling pathway significantly activated following C1QTNF6 silencing.

Conclusions

These results suggest that C1QTNF6 plays an important role in promoting OSCC tumorigenesis, which indicates that C1QTNF6 may comprise a promising therapeutic target for OSCC treatment.
Appendix
Available only for authorised users
Literature
1.
go back to reference Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4–5):309–16.CrossRef Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4–5):309–16.CrossRef
2.
go back to reference Kamarajan P, Garcia-Pardo A, D’Silva NJ, et al. The CS1 segment of fibronectin is involved in human OSCC pathogenesis by mediating OSCC cell spreading, migration, and invasion. BMC Cancer. 2010;10:330.CrossRef Kamarajan P, Garcia-Pardo A, D’Silva NJ, et al. The CS1 segment of fibronectin is involved in human OSCC pathogenesis by mediating OSCC cell spreading, migration, and invasion. BMC Cancer. 2010;10:330.CrossRef
3.
go back to reference Wu CH, Wu TY, Li CC, et al. Impact of diabetes mellitus on the prognosis of patients with oral squamous cell carcinoma: a retrospective cohort study. Ann Surg Oncol. 2010;17(8):2175–83.CrossRef Wu CH, Wu TY, Li CC, et al. Impact of diabetes mellitus on the prognosis of patients with oral squamous cell carcinoma: a retrospective cohort study. Ann Surg Oncol. 2010;17(8):2175–83.CrossRef
4.
go back to reference Klonisch T, Glogowska A, Thanasupawat T, et al. Structural commonality of C1q TNF-related proteins and their potential to activate relaxin/insulin-like family peptide receptor 1 signalling pathways in cancer cells. Br J Pharmacol. 2017;174(10):1025–33.CrossRef Klonisch T, Glogowska A, Thanasupawat T, et al. Structural commonality of C1q TNF-related proteins and their potential to activate relaxin/insulin-like family peptide receptor 1 signalling pathways in cancer cells. Br J Pharmacol. 2017;174(10):1025–33.CrossRef
5.
go back to reference Wong GW, Wang J, Hug C, et al. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA. 2004;101(28):10302–7.CrossRef Wong GW, Wang J, Hug C, et al. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA. 2004;101(28):10302–7.CrossRef
6.
go back to reference Akiyama H, Furukawa S, Wakisaka S, et al. CTRP3/cartducin promotes proliferation and migration of endothelial cells. Mol Cell Biochem. 2007;304(1–2):243–8.CrossRef Akiyama H, Furukawa S, Wakisaka S, et al. CTRP3/cartducin promotes proliferation and migration of endothelial cells. Mol Cell Biochem. 2007;304(1–2):243–8.CrossRef
7.
go back to reference Park SY, Choi JH, Ryu HS, et al. C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase. J Biol Chem. 2009;284(41):27780–9.CrossRef Park SY, Choi JH, Ryu HS, et al. C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase. J Biol Chem. 2009;284(41):27780–9.CrossRef
8.
go back to reference Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem. 2010;285(51):39691–701.CrossRef Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem. 2010;285(51):39691–701.CrossRef
9.
go back to reference Chavali VR, Khan NW, Cukras CA, et al. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration. Hum Mol Genet. 2011;20(10):2000–14.CrossRef Chavali VR, Khan NW, Cukras CA, et al. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration. Hum Mol Genet. 2011;20(10):2000–14.CrossRef
10.
go back to reference Hofmann C, Chen N, Obermeier F, et al. C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts. Inflamm Bowel Dis. 2011;17(12):2462–71.CrossRef Hofmann C, Chen N, Obermeier F, et al. C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts. Inflamm Bowel Dis. 2011;17(12):2462–71.CrossRef
11.
go back to reference Seldin MM, Tan SY, Wong GW. Metabolic function of the CTRP family of hormones. Rev Endocr Metab Disord. 2014;15(2):111–23.CrossRef Seldin MM, Tan SY, Wong GW. Metabolic function of the CTRP family of hormones. Rev Endocr Metab Disord. 2014;15(2):111–23.CrossRef
12.
go back to reference Ghai R, Waters P, Roumenina LT, et al. C1q and its growing family. Immunobiology. 2007;212(4–5):253–66.CrossRef Ghai R, Waters P, Roumenina LT, et al. C1q and its growing family. Immunobiology. 2007;212(4–5):253–66.CrossRef
13.
go back to reference Kim MJ, Lee W, Park EJ, et al. C1qTNF-related protein-6 increases the expression of interleukin-10 in macrophages. Mol Cells. 2010;30(1):59–64.CrossRef Kim MJ, Lee W, Park EJ, et al. C1qTNF-related protein-6 increases the expression of interleukin-10 in macrophages. Mol Cells. 2010;30(1):59–64.CrossRef
14.
go back to reference Lee W, Kim MJ, Park EJ, et al. C1qTNF-related protein-6 mediates fatty acid oxidation via the activation of the AMP-activated protein kinase. FEBS Lett. 2010;584(5):968–72.CrossRef Lee W, Kim MJ, Park EJ, et al. C1qTNF-related protein-6 mediates fatty acid oxidation via the activation of the AMP-activated protein kinase. FEBS Lett. 2010;584(5):968–72.CrossRef
15.
go back to reference Murayama MA, Kakuta S, Inoue A, et al. CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. Nat Commun. 2015;6:8483.CrossRef Murayama MA, Kakuta S, Inoue A, et al. CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. Nat Commun. 2015;6:8483.CrossRef
16.
go back to reference Li Q, Wang L, Tan W, et al. Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-κB pathways and promotes cell survival in human cancer cells. Cancer Lett. 2011;308(2):203–14.CrossRef Li Q, Wang L, Tan W, et al. Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-κB pathways and promotes cell survival in human cancer cells. Cancer Lett. 2011;308(2):203–14.CrossRef
17.
go back to reference Lin W, Chen X, Chen T, et al. C1QTNF6 as a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma. DNA Cell Biol. 2020;39(6):1000–11.CrossRef Lin W, Chen X, Chen T, et al. C1QTNF6 as a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma. DNA Cell Biol. 2020;39(6):1000–11.CrossRef
18.
go back to reference Qu HX, Cui L, Meng XY, et al. C1QTNF6 is overexpressed in gastric carcinoma and contributes to the proliferation and migration of gastric carcinoma cells. Int J Mol Med. 2019;43(1):621–9.PubMed Qu HX, Cui L, Meng XY, et al. C1QTNF6 is overexpressed in gastric carcinoma and contributes to the proliferation and migration of gastric carcinoma cells. Int J Mol Med. 2019;43(1):621–9.PubMed
20.
go back to reference Takeuchi T, Adachi Y, Nagayama T. Expression of a secretory protein C1qTNF6, a C1qTNF family member, in hepatocellular carcinoma. Anal Cell Pathol (Amst). 2011;34(3):113–22.CrossRef Takeuchi T, Adachi Y, Nagayama T. Expression of a secretory protein C1qTNF6, a C1qTNF family member, in hepatocellular carcinoma. Anal Cell Pathol (Amst). 2011;34(3):113–22.CrossRef
21.
go back to reference O’Hanlon DM, Lynch J, Cormican M, et al. The acute phase response in breast carcinoma. Anticancer Res. 2002;22(2b):1289–93.PubMed O’Hanlon DM, Lynch J, Cormican M, et al. The acute phase response in breast carcinoma. Anticancer Res. 2002;22(2b):1289–93.PubMed
22.
go back to reference Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54.CrossRef Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54.CrossRef
23.
go back to reference Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011;48(4):155–70.CrossRef Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011;48(4):155–70.CrossRef
24.
go back to reference Ray K, Ujvari B, Ramana V, et al. Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer. Cytokine Growth Factor Rev. 2018;41:18–27.CrossRef Ray K, Ujvari B, Ramana V, et al. Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer. Cytokine Growth Factor Rev. 2018;41:18–27.CrossRef
25.
go back to reference Shen ZT, Sigalov AB. Novel TREM-1 inhibitors attenuate tumor growth and prolong survival in experimental pancreatic cancer. Mol Pharm. 2017;14(12):4572–82.CrossRef Shen ZT, Sigalov AB. Novel TREM-1 inhibitors attenuate tumor growth and prolong survival in experimental pancreatic cancer. Mol Pharm. 2017;14(12):4572–82.CrossRef
26.
go back to reference Tran TH, Tran TTP, Truong DH, et al. Toll-like receptor-targeted particles: a paradigm to manipulate the tumor microenvironment for cancer immunotherapy. Acta Biomater. 2019;94:82–96.CrossRef Tran TH, Tran TTP, Truong DH, et al. Toll-like receptor-targeted particles: a paradigm to manipulate the tumor microenvironment for cancer immunotherapy. Acta Biomater. 2019;94:82–96.CrossRef
27.
go back to reference Zhao Z, Bo Z, Gong W, et al. Inhibitor of differentiation 1 (Id1) in cancer and cancer therapy. Int J Med Sci. 2020;17(8):995–1005.CrossRef Zhao Z, Bo Z, Gong W, et al. Inhibitor of differentiation 1 (Id1) in cancer and cancer therapy. Int J Med Sci. 2020;17(8):995–1005.CrossRef
28.
go back to reference Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal. 2017;15(1):7.CrossRef Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal. 2017;15(1):7.CrossRef
29.
go back to reference Cheng YJ, Tsai JW, Hsieh KC, et al. Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway. Cancer Lett. 2011;307(2):191–9.CrossRef Cheng YJ, Tsai JW, Hsieh KC, et al. Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway. Cancer Lett. 2011;307(2):191–9.CrossRef
30.
go back to reference Han J, Flemington C, Houghton AB, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA. 2001;98(20):11318–23.CrossRef Han J, Flemington C, Houghton AB, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA. 2001;98(20):11318–23.CrossRef
32.
go back to reference Liu H, Tian Z, Guo Y, et al. Microcystin-leucine arginine exposure contributes to apoptosis and follicular atresia in mice ovaries by endoplasmic reticulum stress-upregulated Ddit3. Sci Total Environ. 2021;756:144070.CrossRef Liu H, Tian Z, Guo Y, et al. Microcystin-leucine arginine exposure contributes to apoptosis and follicular atresia in mice ovaries by endoplasmic reticulum stress-upregulated Ddit3. Sci Total Environ. 2021;756:144070.CrossRef
33.
go back to reference Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13(3):184–90.CrossRef Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13(3):184–90.CrossRef
34.
go back to reference Li Y, Guo Y, Tang J, et al. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin. 2015;47(2):146–7.CrossRef Li Y, Guo Y, Tang J, et al. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin. 2015;47(2):146–7.CrossRef
Metadata
Title
C1QTNF6 promotes oral squamous cell carcinoma by enhancing proliferation and inhibiting apoptosis
Authors
Xiaobin Song
Longjie Li
Liang Shi
Xinyu Liu
Xun Qu
Fengcai Wei
Ketao Wang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02377-x

Other articles of this Issue 1/2021

Cancer Cell International 1/2021 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine