DLC2 operates as a tumor suppressor gene in breast cancer via the RhoGTPase pathway

Yang,Zheng; Chen,Hanrui; Shu,Man; Zhang,Yunjian; Xue,Ling; Lin,Yuan

doi:10.3892/ol.2018.9874

DLC2 operates as a tumor suppressor gene in breast cancer via the RhoGTPase pathway

Authors:
- Zheng Yang
- Hanrui Chen
- Man Shu
- Yunjian Zhang
- Ling Xue
- Yuan Lin
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Affiliations: Department of Pathology, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China, Department of Thyroid, Breast Surgery, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: December 28, 2018 https://doi.org/10.3892/ol.2018.9874
Pages: 2107-2116
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Deleted in liver cancer 2 (DLC2) is a tumor suppressor, associated with various types of cancer. The aim of the present study was to analyze the expression of DLC2 in breast cancer, its clinical significance and its effect on breast cancer cell behavior. The expression of DLC2 was evaluated by immunohistochemistry in 131 cases of breast cancer. Associations among DLC2 expression and clinicopathological features were analyzed, and its effects on proliferation, motility, migration and invasion in DLC2‑knockdown breast cancer cell lines were observed. The results indicated that DLC2 was expressed in 42.75% of breast cancer cases (56/131) and in 79.39% of adjacent normal tissues (104/131). Lower expression of DLC2 in breast cancer was associated with tumor differentiation (P<0.001), lymph node metastasis (P<0.001) and poor prognosis (P<0.001). The silencing of the DLC2 gene in human breast cancer cell indicated an increased number of cells entering S phase, and increased abilities of clone formation, cell migration and invasion. Downregulated expression of DLC2 was associated with activated Ras homolog family member A and decreased Rac family small GTPase 1, cell division cycle 42 and Rho‑associated protein kinase‑2 expression levels, indicating that DLC2 may serve a regulatory function in breast cancer cell proliferation and invasion via the RhoGTPase pathway. The results of the present study suggested that DLC2 serves as a suppressor gene in the development of breast cancer and may be a prognostic marker for patients with breast cancer.

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1	Gray JM, Rasanayagam S, Engel C and Rizzo J: State of the evidence 2017: An update on the connection between breast cancer and the environment. Environ Health. 16:942017. View Article : Google Scholar : PubMed/NCBI
2	Law AMK, Lim E, Ormandy CJ and Gallego-Ortega D: The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy. Endocr Relat Cancer. 24:X12017. View Article : Google Scholar : PubMed/NCBI
3	Li Y, Li S, Meng X, Gan RY, Zhang JJ and Li HB: Dietary natural products for prevention and treatment of breast cancer. Nutrients. 9(pii): E7282017. View Article : Google Scholar : PubMed/NCBI
4	Boix-Perales H, Borregaard J, Jensen KB, Ersbøll J, Galluzzo S, Giuliani R, Ciceroni C, Melchiorri D, Salmonson T, Bergh J, et al: The European medicines agency review of pertuzumab for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer: Summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 19:766–773. 2014. View Article : Google Scholar : PubMed/NCBI
5	Folkman J: Angiogenesis: An organizing principle for drug discovery. Nat Rev Drug Discov. 6:273–286. 2007. View Article : Google Scholar : PubMed/NCBI
6	Carmeliet P: Angiogenesis in health and disease. Nat Med. 9:653–660. 2003. View Article : Google Scholar : PubMed/NCBI
7	Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY and Ng IO: Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem. 278:10824–10830. 2003. View Article : Google Scholar : PubMed/NCBI
8	Vitiello E, Ferreira JG, Maiato H, Balda MS and Matter K: The tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell-cell adhesion. Nat Commun. 5:58262014. View Article : Google Scholar : PubMed/NCBI
9	Chan FK, Chung SS, Ng IO and Chung SK: The RhoA GTPase-activating protein DLC2 modulates RhoA activity and hyperalgesia to noxious thermal and inflammatory stimuli. Neurosignals. 20:112–126. 2012. View Article : Google Scholar : PubMed/NCBI
10	Ullmannova V and Popescu NC: Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol. 29:1127–1132. 2006.PubMed/NCBI
11	Lin Y, Chen NT, Shih YP, Liao YC, Xue L and Lo SH: DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration. Oncogene. 29:3010–3016. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yakirevich E, Magi-Galluzzi C, Grada Z, Lu S, Resnick MB and Mangray S: Cadherin 17 is a sensitive and specific marker for metanephric adenoma. Am J Surg Pathol. 39:479–486. 2015. View Article : Google Scholar : PubMed/NCBI
13	Lakhani SR, Ellis IO, Schnitt SJ, Tan PH and van de Vijver MJ: WHO classification of tumours of the breast. Fourth edition. Int Agency Res Cancer. 9–27. 2016.
14	Hanna S, Khalil B, Nasrallah A, Saykali BA, Sobh R, Nasser S and El-Sibai M: StarD13 is a tumor suppressor in breast cancer that regulates cell motility and invasion. Int J Oncol. 44:1499–1511. 2014. View Article : Google Scholar : PubMed/NCBI
15	El-Sitt S, Khalil BD, Hanna S, El-Sabban M, Fakhreddine N and El-Sibai M: DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma. Oncol Rep. 28:511–518. 2012. View Article : Google Scholar : PubMed/NCBI
16	Leung TH, Yam JW, Chan LK, Ching YP and Ng IO: Deleted in liver cancer 2 suppresses cell growth via the regulation of the Raf-1-ERK1/2-p70S6K signalling pathway. Liver Int. 30:1315–1323. 2010. View Article : Google Scholar : PubMed/NCBI
17	Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY and Ng IO: Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proc Natl Acad Sci USA. 102:15207–15212. 2005. View Article : Google Scholar : PubMed/NCBI
18	Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE, Thorgeirsson SS and Popescu NC: DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene. 22:445–450. 2003. View Article : Google Scholar : PubMed/NCBI
19	Yuan BZ, Jefferson AM, Baldwin KT, Thorgeirsson SS, Popescu NC and Reynolds SH: DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene. 23:1405–1411. 2004. View Article : Google Scholar : PubMed/NCBI
20	Zhou X, Thorgeirsson SS and Popescu NC: Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene. 23:1308–1313. 2004. View Article : Google Scholar : PubMed/NCBI
21	Lukasik D, Wilczek E, Wasiutynski A and Gornicka B: Deleted in liver cancer protein family in human malignancies (Review). Oncol Lett. 2:763–768. 2011.PubMed/NCBI
22	Kawai K, Kiyota M, Seike J, Deki Y and Yagisawa H: START-GAP3/DLC3 is a GAP for RhoA and Cdc42 and is localized in focal adhesions regulating cell morphology. Biochem Biophys Res Commun. 364:783–789. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zheng L, Li X, Chou J, Xiang C, Guo Q, Zhang Z, Guo X, Gao L, Xing Y and Xi T: StarD13 3′-untranslated region functions as a ceRNA for TP53INP1 in prohibiting migration and invasion of breast cancer cells by regulating miR-125b activity. Eur J Cell Biol. 97:23–31. 2018. View Article : Google Scholar : PubMed/NCBI
24	Shih YP, Liao YC, Lin Y and Lo SH: DLC1 negatively regulates angiogenesis in a paracrine fashion. Cancer Res. 70:8270–8275. 2010. View Article : Google Scholar : PubMed/NCBI
25	Tcherkezian J and Lamarche-Vane N: Current knowledge of the large RhoGAP family of proteins. Biol Cell. 99:67–86. 2007. View Article : Google Scholar : PubMed/NCBI
26	Petzold KM, Naumann H and Spagnoli FM: Rho signalling restriction by the RhoGAP Stard13 integrates growth and morphogenesis in the pancreas. Development. 140:126–135. 2013. View Article : Google Scholar : PubMed/NCBI
27	Khalil BD, Hanna S, Saykali BA, El-Sitt S, Nasrallah A, Marston D, El-Sabban M, Hahn KM, Symons M and El-Sibai M: The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility. Exp Cell Res. 321:109–122. 2014. View Article : Google Scholar : PubMed/NCBI
28	Tang F, Zhang R, He Y, Zou M, Guo L and Xi T: MicroRNA-125b induces metastasis by targeting STARD13 in MCF-7 and MDA-MB-231 breast cancer cells. PLoS One. 7:e354352012. View Article : Google Scholar : PubMed/NCBI
29	Li X, Zheng L, Zhang F, Hu J, Chou J, Liu Y, Xing Y and Xi T: STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer. Oncotarget. 7:23197–23211. 2016.PubMed/NCBI
30	Hu J, Li X, Guo X, Guo Q, Xiang C, Zhang Z, Xing Y, Xi T and Zheng L: The CCR2 3′UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis. J Cell Sci. 130:3399–3413. 2017. View Article : Google Scholar : PubMed/NCBI
31	Guo X, Xiang C, Zhang Z, Zhang F, Xi T and Zheng L: Displacement of Bax by BMF Mediates STARD13 3′UTR-induced breast cancer cells apoptosis in an miRNA-depedent manner. Mol Pharm. 15:63–71. 2018. View Article : Google Scholar : PubMed/NCBI
32	Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 31:3997–4013. 2013. View Article : Google Scholar : PubMed/NCBI