DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma

El-Sitt,Sally; Khalil,Bassem  D.; Hanna,Samer; El-Sabban,Marwan; Fakhreddine,Najla; El-Sibai,Mirvat

doi:10.3892/or.2012.1819

DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma

Authors:
- Sally El-Sitt
- Bassem D. Khalil
- Samer Hanna
- Marwan El-Sabban
- Najla Fakhreddine
- Mirvat El-Sibai
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Affiliations: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon, Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon, Department of Pathology, Hammoud Hospital, Saida, Lebanon
Published online on: May 17, 2012 https://doi.org/10.3892/or.2012.1819
Pages: 511-518

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Abstract

Astrocytomas are tumors occurring in young adulthood. Astrocytic tumors can be classified into four grades according to histologic features: grades I, II, III and grade IV. Malignant tumors, those of grades III and IV, are characterized by uncontrolled proliferation, which is known to be regulated by the family of Rho GTPases. StarD13, a GAP for Rho GTPases, has been described as a tumor suppressor in hepatocellular carcinoma. In the present study, IHC analysis on grades I-IV brain tissues from patients showed StarD13 to be overexpressed in grades III and IV astrocytoma tumors when compared to grades I and II. However, when we mined the REMBRANDT data, we found that the mRNA levels of StarD13 are indeed higher in the higher grades but much lower than the normal tissues. Knocking down StarD13 using siRNA led to a decrease in cell death and an increase in cell viability, proving that StarD13 is indeed a tumor suppressor in astrocytomas. This was found to be mainly through cell cycle arrest independently of apoptosis. Finally, we detected an increase in p-ERK in StarD13 knockdown cells, uncovering a potential link between Rho GTPases and ERK activation.

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1	Buckner JC, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ and Uhm JH: Central nervous system tumors. Mayo Clin Proc. 82:1271–1286. 2007. View Article : Google Scholar : PubMed/NCBI
2	Salacz ME, Watson KR and Schomas DA: Glioblastoma: Part I. Current state of affairs. Mol Med. 108:187–194. 2011.PubMed/NCBI
3	Salacz ME, Watson KR and Schomas DA: Glioblastoma. Part II: future directions. Mol Med. 108:289–291. 2011.PubMed/NCBI
4	Louis DN, Ohgaki H, Wiestler OD and Cavenee WK: WHO Classification of Tumours of the Central Nervous System. World Health Organization; 2007
5	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
6	DeAngelis LM: Brain tumors. N Engl J Med. 344:114–123. 2001. View Article : Google Scholar
7	Karlsson R, Pedersen ED, Wang Z and Brakebusch C: Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 1796:91–98. 2009.PubMed/NCBI
8	Boettner B and Van Aelst L: The role of Rho GTPases in disease development. Gene. 286:155–174. 2002. View Article : Google Scholar : PubMed/NCBI
9	Ridley AJ: Rho proteins and cancer. Breast Cancer Res Treat. 84:13–19. 2004. View Article : Google Scholar
10	Hornstein I, Pikarsky E, Groysman M, Amir G, Peylan-Ramu N and Katzav S: The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas. J Pathol. 199:526–533. 2003. View Article : Google Scholar : PubMed/NCBI
11	Wang W, Wyckoff JB, Frohlich VC, et al: Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62:6278–6288. 2002.PubMed/NCBI
12	Kim TY, Vigil D, Der CJ and Juliano RL: Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. Cancer Metastasis Rev. 28:77–83. 2009. View Article : Google Scholar : PubMed/NCBI
13	Kawai K, Seike J, Iino T, et al: START-GAP2/DLC2 is localized in focal adhesions via its N-terminal region. Biochem Biophys Res Commun. 380:736–741. 2009. View Article : Google Scholar : PubMed/NCBI
14	Rittinger K, Walker PA, Eccleston JF, et al: Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP. Nature. 388:693–697. 1997. View Article : Google Scholar : PubMed/NCBI
15	Yau TO, Leung TH, Lam S, et al: Deleted in liver cancer 2 (DLC2) was dispensable for development and its deficiency did not aggravate hepatocarcinogenesis. PLoS One. 4:e65662009. View Article : Google Scholar : PubMed/NCBI
16	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
17	Soccio RE and Breslow JL: StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J Biol Chem. 278:22183–22186. 2003. View Article : Google Scholar : PubMed/NCBI
18	Qian X, Li G, Asmussen HK, et al: Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Proc Natl Acad Sci USA. 104:9012–9017. 2007. View Article : Google Scholar
19	Li H, Fung KL, Jin DY, et al: Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2. Proteins. 67:1154–1166. 2007. View Article : Google Scholar : PubMed/NCBI
20	Liao YC and Lo SH: 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
21	Ching YP, Wong CM, Chan SF, et al: 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
22	Ng DC, Chan SF, Kok KH, et al: Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. FEBS Lett. 580:191–198. 2006. View Article : Google Scholar : PubMed/NCBI
23	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
24	Leung TH, Ching YP, Yam JW, et al: 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
25	Xiaorong L, Wei W, Liyuan Q and Kaiyan Y: Underexpression of deleted in liver cancer 2 (DLC2) is associated with overexpression of RhoA and poor prognosis in hepatocellular carcinoma. BMC Cancer. 8:2052008. View Article : Google Scholar : PubMed/NCBI
26	Shih YP, Takada Y and Lo SH: Silencing of DLC1 upregulates PAI-1 expression and reduces migration in normal prostate cells. Mol Cancer Res. 10:34–39. 2012. View Article : Google Scholar : PubMed/NCBI
27	Leung LH, Wong WK, Cheng AC, et al: A new approach to computing normal tissue complication probability of an intensity-modulated radiotherapy treatment with stereotactic radiotherapy boost of nasopharyngeal carcinoma: a case study. Med Dosim. 36:138–144. 2011. View Article : Google Scholar
28	Zheng B, Fiumara P, Li YV, et al: MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood. 102:1019–1027. 2003. View Article : Google Scholar : PubMed/NCBI