Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

CADM2, as a new target of miR-10b, promotes tumor metastasis through FAK/AKT pathway in hepatocellular carcinoma

Authors: Dongliang Li, Yongjian Zhang, He Zhang, Chao Zhan, Xin Li, Tu Ba, Zini Qiu, Fang E, Guixiang Lv, Chendan Zou, Chuxuan Wang, Lining Si, Chaoxia Zou, Qiang Li, Xu Gao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Cell adhesion molecules (CADMs) comprise of a protein family whose functions include maintenance of cell polarity and tumor suppression. Hypo-expression of CADM2 gene expression has been observed in several cancers including hepatocellular carcinoma (HCC). However, the role and mechanisms of CADM2 in HCC remain unclear.

Methods

The expression of CADM2 and miRNA-10b (miR-10b) in HCC tissues and cell lines were detected using real-time PCR and Western blotting. Immunofluorescence was used to detect Epithelial-mesenchymal transition (EMT) progression in HCC cell lines. Dual-luciferase reporter assay was used to determine miR-10b binding to CADM2 3’UTR. Wound healing assay and Transwell assay were performed to examine the migration and invasion of HCC cells.

Results

We report the effect of CADM2 as a tumor suppressor in HCC. Firstly, we confirmed that CADM2 expression was significantly down regulated in HCC tissues compared to normal tissues according to TCGA data analysis and fresh HCC sample detection. Secondly, overexpression of CADM2 could inhibit EMT process, migratory and invasion ability of HCC cells. Furthermore, the results indicated that CADM2 is a direct target of miR-10b in HCC cells and miR-10b/CADM2 modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC.

Conclusions

Our study demonstrates that miR-10b-CADM2-FAK/AKT axis plays an important role in HCC metastasis, which might be a novel potential therapeutic option for HCC treatment.
Appendix
Available only for authorised users
Literature
1.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, He J, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed
2.
Chen JG, Zhang SW. Liver cancer epidemic in China: past, present and future. Semin Cancer Biol. 2011;21(1):59–69.CrossRefPubMed
3.
4.
Lau WY, Leung TW, Yu SC, Ho SK. Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Ann Surg. 2003;237(2):171–9.PubMedPubMedCentral
5.
Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 2017;
6.
Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.CrossRefPubMed
7.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.CrossRefPubMed
8.
Fu H, He Y, Qi L, Chen L, Luo Y, Chen L, Guo H, et al. cPLA2alpha activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells. Cancer Lett. 2017;403:260–70.CrossRefPubMed
9.
Shen S, Huang K, Wu Y, Ma Y, Wang J, Qin F, Ma J. A miR-135b-TAZ positive feedback loop promotes epithelial-mesenchymal transition (EMT) and tumorigenesis in osteosarcoma. Cancer Lett. 2017;407:32–44.CrossRefPubMed
10.
Biederer T. Bioinformatic characterization of the SynCAM family of immunoglobulin-like domain-containing adhesion molecules. Genomics. 2006;87(1):139–50.CrossRefPubMed
11.
Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP, Murakami Y, et al. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet. 2001;27(4):427–30.CrossRefPubMed
12.
Fukuhara H, Kuramochi M, Fukami T, Kasahara K, Furuhata M, Nobukuni T, Murakami Y, et al. Promoter methylation of TSLC1 and tumor suppression by its gene product in human prostate cancer. Jpn J Cancer Res. 2002;93(6):605–9.CrossRefPubMed
13.
Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, Imamura M, et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res. 2003;63(19):6320–6.PubMed
14.
Takahashi Y, Iwai M, Kawai T, Arakawa A, Ito T, Sakurai-Yageta M, Murakami Y, et al. Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer. 2012;19(3):242–52.CrossRefPubMed
15.
Williams YN, Masuda M, Sakurai-Yageta M, Maruyama T, Shibuya M, Murakami Y. Cell adhesion and prostate tumor-suppressor activity of TSLL2/IGSF4C, an immunoglobulin superfamily molecule homologous to TSLC1/IGSF4. Oncogene. 2006;25(10):1446–53.CrossRefPubMed
16.
Raveh S, Gavert N, Spiegel I, Ben-Ze'ev A. The cell adhesion nectin-like molecules (Necl) 1 and 4 suppress the growth and tumorigenic ability of colon cancer cells. J Cell Biochem. 2009;108(1):326–36.CrossRefPubMed
17.
Nagata M, Sakurai-Yageta M, Yamada D, Goto A, Ito A, Fukuhara H, Murakami Y, et al. Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma. Int J Cancer. 2012;130(6):1329–37.CrossRefPubMed
18.
Chang G, Xu S, Dhir R, Chandran U, O'Keefe DS, Greenberg NM, Gingrich JR. Hypoexpression and epigenetic regulation of candidate tumor suppressor gene CADM-2 in human prostate cancer. Clin Cancer Res. 2010;16(22):5390–401.CrossRefPubMedPubMedCentral
19.
He W, Li X, Xu S, Ai J, Gong Y, Gregg JL, Chang G, et al. Aberrant methylation and loss of CADM2 tumor suppressor expression is associated with human renal cell carcinoma tumor progression. Biochem Biophys Res Commun. 2013;435(4):526–32.CrossRefPubMed
20.
Yang S, Yan HL, Tao QF, Yuan SX, Tang GN, Yang Y, Zhou WP, et al. Low CADM2 expression predicts high recurrence risk of hepatocellular carcinoma patients after hepatectomy. J Cancer Res Clin Oncol. 2014;140(1):109–16.CrossRefPubMed
21.
Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Wang XW, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111.CrossRefPubMed
22.
Jiang X, Ma N, Wang D, Li F, He R, Li D, Cui Y, et al. Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma. Oncotarget. 2015;6(5):3178–94.PubMed
23.
Mahmood MQ, Walters EH, Shukla SD, Weston S, Muller HK, Ward C, Sohal SS. Beta-catenin, twist and snail: transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction. Sci Rep. 2017;7(1):10832.CrossRefPubMedPubMedCentral
24.
Li G, Wu Z, Peng Y, Liu X, Lu J, Wang L, Li XP, et al. MicroRNA-10b induced by Epstein-Barr virus-encoded latent membrane protein-1 promotes the metastasis of human nasopharyngeal carcinoma cells. Cancer Lett. 2010;299(1):29–36.CrossRefPubMed
25.
Tian Y, Luo A, Cai Y, Su Q, Ding F, Chen H, Liu Z. MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J Biol Chem. 2010;285(11):7986–94.CrossRefPubMedPubMedCentral
26.
Han X, Yan S, Weijie Z, Feng W, Liuxing W, Mengquan L, Qingxia F. Critical role of miR-10b in transforming growth factor-beta1-induced epithelial-mesenchymal transition in breast cancer. Cancer Gene Ther. 2014;21(2):60–7.CrossRefPubMed
27.
Zhang L, Sun J, Wang B, Ren JC, Su W, Zhang T. MicroRNA-10b triggers the epithelial-mesenchymal transition (EMT) of laryngeal carcinoma Hep-2 cells by directly targeting the E-cadherin. Appl Biochem Biotechnol. 2015;176(1):33–44.CrossRefPubMed
28.
Zhang P, Hong H, Sun X, Jiang H, Ma S, Zhao S, Liu H, et al. MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells. Am J Cancer Res. 2016;6(2):141–56.PubMedPubMedCentral
29.
Cody NA, Shen Z, Ripeau JS, Provencher DM, Mes-Masson AM, Chevrette M, Tonin PN. Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer. Mol Carcinog. 2009;48(12):1077–92.CrossRefPubMed
30.
Nakahata S, Saito Y, Marutsuka K, Hidaka T, Maeda K, Hatakeyama K, Morishita K, et al. Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma. Leukemia. 2012;26(6):1238–46.CrossRefPubMed
31.
Li X, Liang L, Zhang M, Song F, Nan H, Wang LE, Han J, et al. Obesity-related genetic variants, human pigmentation, and risk of melanoma. Hum Genet. 2013;132(7):793–801.CrossRefPubMedPubMedCentral
32.
33.
Park JK, Kogure T, Nuovo GJ, Jiang J, He L, Kim JH, Schmittgen TD, et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011;71(24):7608–16.CrossRefPubMedPubMedCentral
34.
Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y, Zhuang SM. MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009;69(3):1135–42.CrossRefPubMed
35.
Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, Gao X, et al. MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget. 2016;7(1):266–78.CrossRefPubMed
36.
Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Wang XW, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897–907.CrossRefPubMed
37.
Liu Y, Ma Y, Zhang J, Xie Q, Wang Z, Yu S, Liu C, et al. MBG-modified beta-TCP scaffold promotes mesenchymal stem cells adhesion and osteogenic differentiation via a FAK/MAPK signaling pathway. ACS Appl Mater Interfaces. 2017;9(36):30283–96.CrossRefPubMed
38.
Lu X, Han J, Xu X, Xu J, Liu L, Huang Y, Qiu H, et al. PGE2 promotes the migration of mesenchymal stem cells through the activation of FAK and ERK1/2 pathway. Stem Cells Int. 2017;2017:8178643.PubMedPubMedCentral
39.
Wang X, Zhou Q, Yu Z, Wu X, Chen X, Li J, Su L, et al. Cancer-associated fibroblast-derived Lumican promotes gastric cancer progression via the integrin beta1-FAK signaling pathway. Int J Cancer. 2017;141(5):998–1010.CrossRefPubMed
40.
Zhao X, Guan JL. Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev. 2011;63(8):610–5.CrossRefPubMed
41.
Hess AR, Postovit LM, Margaryan NV, Seftor EA, Schneider GB, Seftor RE, Hendrix MJ, et al. Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res. 2005;65(21):9851–60.CrossRefPubMed
42.
Lin K, Baritaki S, Militello L, Malaponte G, Bevelacqua Y, Bonavida B. The role of B-RAF mutations in melanoma and the induction of EMT via dysregulation of the NF-kappaB/snail/RKIP/PTEN circuit. Genes Cancer. 2010;1(5):409–20.CrossRefPubMedPubMedCentral
Metadata
Title
CADM2, as a new target of miR-10b, promotes tumor metastasis through FAK/AKT pathway in hepatocellular carcinoma
Authors
Dongliang Li
Yongjian Zhang
He Zhang
Chao Zhan
Xin Li
Tu Ba
Zini Qiu
Fang E
Guixiang Lv
Chendan Zou
Chuxuan Wang
Lining Si
Chaoxia Zou
Qiang Li
Xu Gao
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0699-1

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

Paired box 8 suppresses tumor angiogenesis and metastasis in gastric cancer through repression of FOXM1 via induction of microRNA-612

Research

RETRACTED ARTICLE: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis

Research

Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

Research

RETRACTED ARTICLE: Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Review

The role of cellular reactive oxygen species in cancer chemotherapy

Research

Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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
Image Credits