Open Access

High expression of DLC family proteins predicts better prognosis and inhibits tumor progression in NSCLC

  • Authors:
    • Li Sun
    • Jing Sun
    • Jun‑Ding Song
  • View Affiliations

  • Published online on: April 10, 2019     https://doi.org/10.3892/mmr.2019.10146
  • Pages: 4881-4889
  • Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The incidence of primary lung cancer (PLC) is increasing and is becoming a leading cause of cancer‑associated mortality worldwide. Non‑small cell lung cancer (NSCLC) accounts for ~80% of PLC cases and has the worst prognosis among malignant tumors. Deleted in liver cancer (DLC) proteins belong to the RhoGTPase‑activating protein family and are considered to be tumor suppressor genes. However, the role of the proteins, particularly DLC2 and DLC3, in NSCLC, has not been fully elucidated. The present study investigated the expression levels and prognostic values of DLCs in NSCLC using The Cancer Genome Atlas, the Genotype‑Tissue Expression project and Kaplan‑Meier plotter datasets. The current study demonstrated that the three DLCs were downregulated in NSCLC. High expression levels of DLC1 and DLC2 were associated with an improved survival in NSCLC. Additionally, the effects of DLCs on the proliferation and apoptosis of the lung cancer cell line A‑549 were investigated in vitro using a Cell Counting Kit‑8 assay and flow cytometry analysis. DLC2 and DLC3 overexpression inhibited proliferation and induced apoptosis in A549 cells. To the best of our knowledge, the current study was the first to investigate the expression level and prognostic values of DLC2 and DLC3 in NSCLC. The results indicated that DLC1 DLC2 and DLC3 serve specific roles in the occurrence and development of NSCLC, and may be considered as potential prognostic indicators in NSCLC.

References

1 

Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Travis WD, Travis LB and Devesa SS: Lung cancer. Cancer. 75 (Suppl 1):S191–S202. 1995. View Article : Google Scholar

3 

Yu DP, Bai LQ, Xu SF, Han M and Wang ZT: Impact of TNM staging and treatment mode on the prognosis of non-small cell lung cancer. Zhonghua Zhong Liu Za Zhi. 31:465–468. 2009.(In Chinese). PubMed/NCBI

4 

Quejada MI and Albain KS: Prognostic factors in non-small cell lung cancer. 2004. View Article : Google Scholar

5 

Putila J, Remick SC and Guo NL: Combining clinical, pathological, and demographic factors refines prognosis of lung cancer: A population-based study. PLoS One. 6:e174932011. View Article : Google Scholar : PubMed/NCBI

6 

Minamiya Y, Miura M, Hinai Y, Saito H, Ito M, Imai K, Ono T, Motoyama S and Ogawa J: The CRP 1846T/T genotype is associated with a poor prognosis in patients with non-small cell lung cancer. Tumour Biol. 31:673–679. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 372:2018–2028. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, Watanabe H, Wu YL, Zielinski M, Ball D, et al: The International Association for the study of lung cancer lung cancer staging project: Proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 10:1675–1684. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Ko C: Molecular regulation of deleted in liver cancer (DLC) protein family. The University of Hong Kong; Pokfulam, Hong Kong: 2009, View Article : Google Scholar

10 

Chan L: Protein interaction and the subcellular localization control of the deleted in liver cancer (DLC) family protein. Hku Theses Online. 2008.

11 

Basak P, Dillon R, Leslie H, Raouf A and Mowat MR: The deleted in liver Cancer 1 (Dlc1) tumor suppressor is haploinsufficient for mammary gland development and epithelial cell polarity. BMC Cancer. 15:6302015. View Article : Google Scholar : PubMed/NCBI

12 

Song LJ, Liu Q, Meng XR, Li SL, Wang LX, Fan QX and Xuan XY: DLC-1 is an independent prognostic marker and potential therapeutic target in hepatocellular cancer. Diagn Pathol. 11:192016. View Article : Google Scholar : PubMed/NCBI

13 

Ortega CE, Seidner Y and Dominguez I: Mining CK2 in cancer. PLoS One. 9:e1156092014. View Article : Google Scholar : PubMed/NCBI

14 

Dötsch MM, Kloten V, Schlensog M, Heide T, Braunschweig T, Veeck J, Petersen I, Knüchel R and Dahl E: Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome. Epigenetics. 10:903–912. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Tilghman SL, Townley I, Zhong Q, Carriere PP, Zou J, Llopis SD, Preyan LC, Williams CC, Skripnikova E, Bratton MR, et al: Proteomic signatures of acquired letrozole resistance in breast cancer: Suppressed estrogen signaling and increased cell motility and invasiveness. Mol Cell Proteomics. 12:2440–2455. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Zhang S, Wang Z, Liu W, Lei R, Shan J, Li L and Wang X: Distinct prognostic values of S100 mRNA expression in breast cancer. Sci Rep. 7:397862017. View Article : Google Scholar : PubMed/NCBI

17 

Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Li M, Li S, Liu B, Gu MM, Zou S, Xiao BB, Yu L, Ding WQ, Zhou PK, Zhou J and Shang ZF: PIG3 promotes NSCLC cell mitotic progression and is associated with poor prognosis of NSCLC patients. J Exp Clin Cancer Res. 36:392017. View Article : Google Scholar : PubMed/NCBI

19 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Yuan BZ, Jefferson AM, Millecchia L, Popescu NC and Reynolds SH: Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells. Exp Cell Res. 313:3868–3880. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Bokoch GM, Bohl BP and Chuang TH: Guanine nucleotide exchange regulates membrane translocation of Rac/Rho GTP-binding proteins. J Biol Chem. 269:31674–31679. 1994.PubMed/NCBI

22 

Goodison S, Yuan J, Sloan D, Kim R, Li C, Popescu NC and Urquidi V: The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells. Cancer Res. 65:6042–6053. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Liao YC and Su HL: Deleted in liver cancer-1 (DLC-1): A tumor suppressor not just for liver. Int J Biochem Cell Biol. 40:843–847. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Durkin ME, Ullmannova V, Guan M and Popescu NC: Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth. Oncogene. 26:4580–4589. 2007. View Article : Google Scholar : PubMed/NCBI

25 

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

26 

Zhong D, Zhang J, Yang S, Soh UJ, Buschdorf JP, Zhou YT, Yang D and Low BC: The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration. J Cell Sci. 122:414–424. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Healy KD, Hodgson L, Kim TY, Shutes A, Maddileti S, Juliano RL, Hahn KM, Harden TK, Bang YJ and Der CJ: DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Mol Carcinog. 47:326–337. 2008. View Article : Google Scholar : PubMed/NCBI

28 

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

29 

Kim TY, Lee JW, Kim HP, Jong HS, Kim TY, Jung M and Bang YJ: DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma. Biochem Biophys Res Commun. 355:72–77. 2007. View Article : Google Scholar : PubMed/NCBI

30 

Durkin ME, Avner MR, Huh CG, Yuan BZ, Thorgeirsson SS and Popescu NC: DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS Lett. 579:1191–1196. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Wang D, Qian X, Rajaram M, Durkin ME and Lowy DR: DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers. Oncotarget. 7:45144–45157. 2016.PubMed/NCBI

32 

Wu PP, Zhu HY, Sun XF, Chen LX, Zhou Q and Chen J: MicroRNA-141 regulates the tumour suppressor DLC1 in colorectal cancer. Neoplasma. 62:705–712. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS and Popescu NC: Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res. 58:2196–2199. 1998.PubMed/NCBI

34 

Park H, Cho SY, Kim H, Na D, Han JY, Chae J, Park C, Park OK, Min S, Kang J, et al: Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proc Natl Acad Sci USA. 112:12492–12497. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Feng H, Zhang Z, Wang X and Liu D: Identification of DLC-1 expression and methylation status in patients with non-small-cell lung cancer. Mol Clin Oncol. 4:249–254. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Healy KD, Tai YK, Shutes AT, Bang YJ, Juliano RL and Der CJ: RhoGAP DLC-1 tumor suppression and aberrant Rho GTPase activation in lung cancer. Cancer Res. 66:2006.

37 

Du X, Qian X, Papageorge A, Schetter AJ, Vass WC, Liu X, Braverman R, Robles AI and Lowy DR: Functional interaction of tumor suppressor DLC1 and caveolin-1 in cancer cells. Cancer Res. 72:4405–4416. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Yang X, Popescu NC and Zimonjic DB: DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism. Cancer Res. 71:2916–2925. 2011. View Article : Google Scholar : PubMed/NCBI

39 

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

40 

de Tayrac M, Etcheverry A, Aubry M, Saïkali S, Hamlat A, Quillien V, Le Treut A, Galibert MD and Mosser J: Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression. Genes Chromosomes Cancer. 48:55–68. 2009. View Article : Google Scholar : PubMed/NCBI

41 

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

42 

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

43 

Wolosz D, Szparecki G, Wolinska E and Gornicka B: DLC3 expression in hepatocellular carcinoma. J Pre Clin Clin Res. 9:105–108. 2015. View Article : Google Scholar

44 

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

45 

Hendrick J and Olayioye MA: Spatial Rho regulation: Molecular mechanisms controlling the GAP protein DLC3. Small GTPases. 1–7. 2016.PubMed/NCBI

46 

Braun AC, Hendrick J, Eisler SA, Schmid S, Hausser A and Olayioye MA: The Rho-specific GAP protein DLC3 coordinates endocytic membrane trafficking. J Cell Sci. 128:1386–1399. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Braun AC: Regulation of endocytic membrane trafficking by the GTPase-activating protein deleted in liver cancer 3 (DLC3). Uni Stuttgart. 2015.

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Copy and paste a formatted citation
APA
Sun, L., Sun, J., & Song, J. (2019). High expression of DLC family proteins predicts better prognosis and inhibits tumor progression in NSCLC. Molecular Medicine Reports, 19, 4881-4889. https://doi.org/10.3892/mmr.2019.10146
MLA
Sun, L., Sun, J., Song, J."High expression of DLC family proteins predicts better prognosis and inhibits tumor progression in NSCLC". Molecular Medicine Reports 19.6 (2019): 4881-4889.
Chicago
Sun, L., Sun, J., Song, J."High expression of DLC family proteins predicts better prognosis and inhibits tumor progression in NSCLC". Molecular Medicine Reports 19, no. 6 (2019): 4881-4889. https://doi.org/10.3892/mmr.2019.10146