Abstract
Prostate cancer is the second most commonly diagnosed cancer in men and one of the main leading causes of cancer deaths among men worldwide. Rapid uncontrolled growth and the ability to metastasize to other sites are key hallmarks in cancer development and progression. The Rho family of GTPases and its activators the GTPase-activating proteins (GAPs) are required for regulating cancer cell proliferation and migration. StarD13 is a GAP for Rho GTPases, specifically for RhoA and Cdc42. We have previously shown that StarD13 acts as a tumor suppressor in astrocytoma as well as breast and colorectal cancer. In this study, we performed a functional comparative analysis of StarD13 targets/and or interacting molecules to understand the general role that StarD13 plays in cancers. Our data highlight the importance of StarD13 in modulating several hallmarks of cancer. Findings from database mining and immunohistochemistry revealed that StarD13 is underexpressed in prostate cancers, in addition knocking down Stard13 increased cancer cell proliferation, consistent with its role as a tumor suppressor. Stard13 depletion, however, led to an increase in cell adhesion, which inhibited 2D cell migration. Most interestingly, StarD13 depletion increases invasion and matrix degradation, at least in part, through its regulation of Cdc42. Altogether, the data presented suggest that StarD13 acts as a tumor suppressor inhibiting prostate cancer cell invasion.
Similar content being viewed by others
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Key statistics for prostate cancer | prostate cancer facts. American Cancer Society 2020. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html
Christofori G. New signals from the invasive front. Nature. 2006;441:444–50.
Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.
Zeeshan R, Mutahir Z. Cancer metastasis—tricks of the trade. Bosn J Basic Med Sci. 2017;17:172–82.
Alblazi KM, Siar CH. Cellular protrusions–lamellipodia, filopodia, invadopodia and podosomes–and their roles in progression of orofacial tumours: current understanding. Asian Pac J Cancer Prev. 2015;16:2187–91.
Bailly M, Condeelis J. Cell motility: insights from the backstage. Nat Cell Biol. 2002;4:E292–4.
Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell. 1996;84:359–69.
Michaelis UR. Mechanisms of endothelial cell migration. Cell Mol Life Sci. 2014;71:4131–48.
Hanna S, El-Sibai M. Signaling networks of Rho GTPases in cell motility. Cell Signal. 2013;25:1955–61.
Al-Koussa H, Atat OE, Jaafar L, Tashjian H, El-Sibai M. The role of Rho GTPases in motility and invasion of glioblastoma cells. Anal Cell Pathol (Amst). 2020;2020:9274016.
Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701.
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. 2003;278:10824–30.
Ridley AJ. Rho GTPase signalling in cell migration. Curr Opin Cell Biol. 2015;36:103–12.
Alan JK, Lundquist EA. Mutationally activated Rho GTPases in cancer. Small GTPases. 2013;4:159–63.
El-Sitt S, El-Sibai M. The STAR of the DLC family. J Recept Signal Transduct Res. 2013;33:10–3.
El-Sitt S, Khalil BD, Hanna S, El-Sabban M, Fakhreddine N, El-Sibai M. DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma. Oncol Rep. 2012;28:511–8.
Gao F, Yu X, Meng R, Wang J, Jia L. STARD13 is positively correlated with good prognosis and enhances 5-FU sensitivity via suppressing cancer stemness in hepatocellular carcinoma cells. Onco Targets Ther. 2018;11:5371–81.
Jaafar L, Chamseddine Z, El-Sibai M. StarD13: a potential star target for tumor therapeutics. Hum Cell. 2020;33:437–43.
Leung TH, Yam JW, Chan LK, Ching YP, Ng IO. Deleted in liver cancer 2 suppresses cell growth via the regulation of the Raf-1-ERK1/2-p70S6K signalling pathway. Liver Int. 2010;30:1315–23.
Guo X, Xiang C, Zhang Z, Zhang F, Xi T, Zheng L. Displacement of bax by BMF mediates STARD13 3’UTR-induced breast cancer cells apoptosis in an miRNA-depedent manner. Mol Pharm. 2018;15:63–71.
Ullmannova V, Popescu NC. Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol. 2006;29:1127–32.
Basak P, Leslie H, Dillon RL, Muller WJ, Raouf A, Mowat MRA. In vivo evidence supporting a metastasis suppressor role for Stard13 (Dlc2) in ErbB2 (Neu) oncogene induced mouse mammary tumors. Genes Chromosomes Cancer. 2018;57:182–91.
Hanna S, Khalil B, Nasrallah A, et al. StarD13 is a tumor suppressor in breast cancer that regulates cell motility and invasion. Int J Oncol. 2014;44:1499–511.
Li X, Zheng L, Zhang F, et al. STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer. Oncotarget. 2016;7:23197–211.
Nasrallah A, Saykali B, Al Dimassi S, Khoury N, Hanna S, El-Sibai M. Effect of StarD13 on colorectal cancer proliferation, motility and invasion. Oncol Rep. 2014;31:505–15.
Yang B, Zhou SN, Tan JN, et al. Long non-coding RNA STARD13-AS suppresses cell proliferation and metastasis in colorectal cancer. Onco Targets Ther. 2019;12:9309–18.
Zhou G, Liu X, Xiong B, Sun Y. Homeobox B4 inhibits breast cancer cell migration by directly binding to StAR-related lipid transfer domain protein 13. Oncol Lett. 2017;14:4625–32.
Chen L, Hu W, Li G, Guo Y, Wan Z, Yu J. Inhibition of miR-9-5p suppresses prostate cancer progress by targeting StarD13. Cell Mol Biol Lett. 2019;24:20.
Al Hassan M, Fakhoury I, El Masri Z, et al. Metformin treatment inhibits motility and invasion of glioblastoma cancer cells. Anal Cell Pathol (Amst). 2018;2018:5917470.
Al-Dimassi S, Salloum G, Saykali B, et al. Targeting the MAP kinase pathway in astrocytoma cells using a recombinant anthrax lethal toxin as a way to inhibit cell motility and invasion. Int J Oncol. 2016;48:1913–20.
Nicolas S, Abdellatef S, Haddad MA, Fakhoury I, El-Sibai M. Hypoxia and EGF stimulation regulate VEGF Expression in human glioblastoma multiforme (GBM) cells by differential regulation of the PI3K/Rho-GTPase and MAPK Pathways. Cells. 2019; 8.
Jalaleddine N, El-Hajjar L, Dakik H, et al. Pannexin1 is associated with enhanced epithelial-to-mesenchymal transition in human patient breast cancer tissues and in breast cancer cell lines. Cancers. 2019;11:1967.
Yamaguchi H, Lorenz M, Kempiak S, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol. 2005;168:441–52.
Iizuka S, Abdullah C, Buschman MD, Diaz B, Courtneidge SA. The role of Tks adaptor proteins in invadopodia formation, growth and metastasis of melanoma. Oncotarget. 2016;7:78473–86.
Zheng L, Li X, Chou J, et al. 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. 2018;97:23–31.
Bishop AL, Hall A. Rho GTPases and their effector proteins. Biochem J. 2000;348(Pt 2):241–55.
Boettner B, Van Aelst L. The role of Rho GTPases in disease development. Gene. 2002;286:155–74.
Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005;21:247–69.
Parsons JT, Horwitz AR, Schwartz MA. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat Rev Mol Cell Biol. 2010;11:633–43.
Hankins GR, Sasaki T, Lieu AS, et al. Identification of the deleted in liver cancer 1 gene, DLC1, as a candidate meningioma tumor suppressor. Neurosurgery. 2008; 63:771–80; discussion 80–1.
de Tayrac M, Etcheverry A, Aubry M, et al. Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression. Genes Chromosomes Cancer. 2009;48:55–68.
Wang D, Qian X, Rajaram M, Durkin ME, Lowy DR. DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers. Oncotarget. 2016;7:45144–57.
Wolosz D, Walczak A, Szparecki G, et al. Deleted in Liver Cancer 2 (DLC2) protein expression in hepatocellular carcinoma. Eur J Histochem. 2019; 63.
Sun L, Sun J, Song JD. High expression of DLC family proteins predicts better prognosis and inhibits tumor progression in NSCLC. Mol Med Rep. 2019;19:4881–9.
Zhang H, Wang F, Hu Y. STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas. Biotechnol Lett. 2017;39:207–17.
Lu Z, Jiang G, Blume-Jensen P, Hunter T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol. 2001;21:4016–31.
Okabe H, Aoki K, Yogosawa S, Saito M, Marumo K, Yoshida K. Downregulation of CD24 suppresses bone metastasis of lung cancer. Cancer Sci. 2018;109:112–20.
Tang H, Jiang L, Zhu C, et al. Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma. Oncogene. 2019;38:3119–33.
Saykali BA, El-Sibai M. Invadopodia, regulation, and assembly in cancer cell invasion. Cell Commun Adhes. 2014;21:207–12.
Steeg PS. Targeting metastasis. Nature reviews. Cancer. 2016;16:201–18.
Gardel ML, Schneider IC, Aratyn-Schaus Y, Waterman CM. Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev Cell Dev Biol. 2010;26:315–33.
Khalil BD, Hanna S, Saykali BA, et al. The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility. Exp Cell Res. 2014;321:109–22.
Al Haddad M, El-Rif R, Hanna S, et al. Differential regulation of rho GTPases during lung adenocarcinoma migration and invasion reveals a novel role of the tumor suppressor StarD13 in invadopodia regulation. Cell Commun Signal. 2020;18:144.
Stengel K, Zheng Y. Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal. 2011;23:1415–23.
Courtneidge SA, Azucena EF, Pass I, Seals DF, Tesfay L. The SRC substrate Tks5, podosomes (invadopodia), and cancer cell invasion. Cold Spring Harb Symp Quant Biol. 2005;70:167–71.
el Lalani N, Laniado ME, Abel PD. Molecular and cellular biology of prostate cancer. Cancer Metastasis Rev. 1997;16:29–66.
Saraon P, Drabovich AP, Jarvi KA, Diamandis EP. Mechanisms of androgen-independent prostate cancer. EJIFCC. 2014;25:42–54.
Zheng L, Zhang Z, Zhang S, Guo Q, Zhang F, Gao L, Ni H, Guo X, Xiang C, Xi T. RNA binding protein RNPC1 inhibits breast cancer cell metastasis via activating STARD13-correlated ceRNA network. Mol Pharm. 2018;15(6):2123–32.
Zheng L, Xiang C, Li X, Guo Q, Gao L, Ni H, Xia Y, Xi T. STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling. J Hematol Oncol. 2018;11(1):72.
Takaoka M, Ito S, Miki Y, Nakanishi A. FKBP51 regulates cell motility and invasion via RhoA signaling. Cancer Sci. 2017;108(3):380–9.
Hu R, Zhu X, Chen C, Xu R, Li Y, Xu W. RNA-binding protein PUM2 suppresses osteosarcoma progression via partly and competitively binding to STARD13 3’UTR with miRNAs. Cell Prolif. 2018;51(6):e12508.
Acknowledgements
This work was funded by the Department of Natural Sciences at the Lebanese American University and by the School of Arts and Science Research and Development Council (SRDC) at LAU.
Funding
This work was supported by the Natural Science Department at the Lebanese American University and by the School of Arts and Science Research and Development Council (SRDC) at LAU.
Author information
Authors and Affiliations
Contributions
LJ performed experiments and data analysis, IF performed experiments and data analysis and wrote the manuscript, SS performed experiments, WA-K provided intellectual and technical guidance, ME-S is the principal investigator who designed the study, provided funds, critical data analysis and discussion and edited the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file2 (AVI 2149 KB)
Supplementary file3 (AVI 10570 KB)
Rights and permissions
About this article
Cite this article
Jaafar, L., Fakhoury, I., Saab, S. et al. StarD13 differentially regulates migration and invasion in prostate cancer cells. Human Cell 34, 607–623 (2021). https://doi.org/10.1007/s13577-020-00479-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13577-020-00479-8