Open Access

Filamin A regulates EGFR/ERK/Akt signaling and affects colorectal cancer cell growth and migration

  • Authors:
    • Kun Wang
    • Tie‑Nian Zhu
    • Rui‑Jing Zhao
  • View Affiliations

  • Published online on: August 27, 2019     https://doi.org/10.3892/mmr.2019.10622
  • Pages: 3671-3678
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The metastasis and recurrence rate, and the overall prognosis of colorectal cancer (CRC) remain unsatisfactory. Filamin A (FLNa), as an actin‑binding protein, can interact with various signaling molecules and membrane receptors to affect cell signal transduction and function. However, whether FLNa is involved in the progression of CRC remains to be elucidated. The aim of the present study was to explore the role of FLNa in CRC cell proliferation and migration, as well as in the regulation of epidermal growth factor receptor (EGFR) signaling. Following transfection with a FLNa‑targeting short hairpin RNA plasmid to knockdown expression of FLNa in the EGF‑treated SW480 cell line, it was found that decreased expression of FLNa promoted cell proliferation and migration. Additionally, there was a negative correlation between FLNa levels and the activation of EGFR and Akt signaling pathways. Similarly, the expression of FLNa was significantly lower in human CRC tissues compared with adjacent normal tissues and FLNa expression was negatively correlated with the expression of Ki‑67 in human CRC tissues. Although there was no significant difference in the Kaplan‑Meier estimate of CRC between high expression and low expression of FLNa, there were significant negative associations between FLNa expression and TNM stage. The results suggested that FLNa may participate in EGF‑induced cell proliferation and migration in CRC cells. Hence, interventions in the FLNa‑mediated signaling pathway could provide attractive therapeutic targets for CRC.

References

1 

Ferlay J, Steliarova-Foucher E, Lortet Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D and Bray F: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 49:1374–1403. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Naishadham D and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Sinclair P, Singh A, Riaz AA and Amin A: An unsolved conundrum: The ideal follow up strategy after curative surgery for colorectal cancer. Gastrointest Endosc. 75:1072–1079. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med. 319:525–532. 1988. View Article : Google Scholar : PubMed/NCBI

5 

Fan N, Kang R, Ge X, Li M, Liu Y, Chen HM and Gao CF: Identification of alpha-2-HS-glycoprotein precursor and tubulin beta chain as serology diagnosis biomarker of colorectal cancer. Diagn Pathol. 12:532014. View Article : Google Scholar

6 

Thomson DM, Krupey J, Freedman SO and Gold P: The radioimmunoassay of circulating carcinoma bryonic antigen of the human digestive system. Proc Natl Acad USA. 64:161–167. 1969. View Article : Google Scholar

7 

Duffy MJ: Role of tumor markers in patients with solid cancers: A critical review. Eur J Intern Med. 18:175–184. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Hartwig JH and Stossel TP: Isolation and properties of actin, myosin and a new actin-binding protein in rabbit alveolar macrophages. J Biol Chem. 250:5696–5705. 1975.PubMed/NCBI

10 

Stossel TP, Condeelis J, Cooley L, Hartwig JH, Noegel A, Schleicher M and Shapiro SS: Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol. 2:138–145. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Gomer RH and Lazarides E: Switching of filamin polypeptides during myogenesis in vitro. J Cell Biol. 96:321–329. 1983. View Article : Google Scholar : PubMed/NCBI

12 

Savoy RM and Ghosh PM: The dual role of filamin a in cancer: Can't live with (too much of) it, can't live without it. Endocr Relat Cancer. 20:R341–R356. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Djinovic-Carugo K and Carugo O: Structural portrait of filamin interaction mechanisms. Cur Protein Pept Sci. 11:639–650. 2010. View Article : Google Scholar

14 

Xu YJ, Bismar TA, Su J, Xu B, Kristiansen G, Varga Z, Teng L, Ingber DE, Mammoto A, Kumar R and Alaoui-Jamali MA: Filamin a regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion. J Exp Med. 207:2421–2437. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ and Walsh CA: Filamin a (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci USA. 103:19836–19841. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Wang Y, Kreisberg JI, Bedolla RG, Mikhailova M, deVere White RW and Ghosh PM: A 90 kDa fragment of filamin A promotes casodex-induced growth inhibition in Casodex-resistant and rogen receptor positive C4-2 prostate cancer cells. Oncogene. 26:6061–6070. 2006. View Article : Google Scholar

17 

Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, Toquet C, Roy E, McGregor L, Lynch SA, et al: Mutations in the gene encoding filamin a as a cause for familial cardiac valvular dystrophy. Circulation. 115:40–49. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Nakamura F, Heikkinen O, Pentikainen OT, Osborn TM, Kasza KE, Weitz DA, Kupiainen O, Permi P, Kilpeläinen I, Ylänne J, et al: Molecular basis of filamin A-FilGAP interaction and its impairment in congenital disorders associated with filamin a mutations. PLoS One. 4:e49282009. View Article : Google Scholar : PubMed/NCBI

19 

Zhou AX, Hartwig JH and Akyurek LM: Filamins in cell signaling transcription and organ development. Trends Cell Biol. 20:113–123. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Zhu TN, He HJ, Kole S, D'Souza T, Agarwal R, Morin PJ and Bernier M: Filamin A-mediated downregulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells. J Biol Chem. 282:14816–14826. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biology. 2:127–137. 2001. View Article : Google Scholar

22 

Roskoski R: The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 79:34–74. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Yewale C, Baradia D, Vhora I, Patil S and Misra A: Epidermal growth factor receptor targeting in cancer: A review of trends and strategies. Biomaterials. 34:8690–8707. 2013. View Article : Google Scholar : PubMed/NCBI

24 

David II, Gallo RM and Settleman J: Mutational activation of ErbB family receptor tyrosine kinases: Insights into mechanisms of signal transduction and tumorigenesis. Bioessays. 29:558–565. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Lo HW: EGFR targeted therapy in malignant Glioma: Novel aspects and mechanisms of drug resistance. Curr Mol Pharmacol. 3:37–52. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Navolanic PM, Steelman LS and McCubrey JA: EGFR family signaling and its association with breast cancer development and resistance to chemotherapy. Int J Oncol. 22:237–252. 2003.PubMed/NCBI

27 

Park OK, Schaefer TS and Nathans D: In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci USA. 93:13704–13708. 1996. View Article : Google Scholar : PubMed/NCBI

28 

Bowman T, Garcia R, Turkson J and Jove R: STATs in oncogenesis. Oncogene. 19:2474–2488. 2013. View Article : Google Scholar

29 

Mclendon RE, Turner K, Perkinson K and Rich J: Second messenger systems in human gliomas. Arch Pathol Lab Med. 131:1585–1590. 2007.PubMed/NCBI

30 

Wang CZ, Xie JT, Zhang B, Ni M, Fishbein A, Aung HH, Mehendale SR, Du W, He TC and Yuan CS: Chemopreventive effects of Panax notoginseng and its major constituents on SW480 human colorectal cancer cells. Int J Oncol. 31:1149–1156. 2007.PubMed/NCBI

31 

Kaleağasıoğlu F and Berger MR: Differential effects of erufosine on proliferation, wound healing and apoptosis in colorectal cancer cell lines. Oncol Rep. 31:1407–1416. 2014. View Article : Google Scholar : PubMed/NCBI

32 

LI K, Zhou ZY, JI PP and Luo HS: Knockdown of β-catenin by siRNA influences proliferation, apoptosis and invasion of the colon cancer cell line SW480. Oncol Lett. 11:3896–3900. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Nakano H, Miyazawa T, Kinoshita K, Yamada Y and Yoshida T: Functional screening identifies a microRNA, miR-491 that induces apoptosis by targeting Bcl-X(L) in colorectal cancer cells. Int J Cancer. 127:1072–1080. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Cardoso AP, Pinto ML, Pinto AT, Oliveira MI, Pinto MT, Gonçalves R, Relvas JB, Figueiredo C, Seruca R, Mantovani A, et al: Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and akt phosphorylation and smallGTPase activity. Oncogene. 33:2123–2133. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Begonja AJ, Hoffmeister KM, Hartwig JH and Falet H: FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly. Blood. 118:2285–2295. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Popowicz GM, Schleicher M, Noegel AA and Holak TA: Filamins: Promiscuous organizers of the cytoskeleton. Trends Biochem Sci. 31:411–419. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Martin GS: Cell signaling and cancer. Cancer Cell. 4:167–174. 2003. View Article : Google Scholar : PubMed/NCBI

38 

Wang K, Ash JF and Singer SJ: Filamin, a new high-molecular- weight protein found in smooth muscle and nonmuscle cells. Proc Natl Acad Sci USA. 72:4483–4486. 1977. View Article : Google Scholar

39 

Ehrlicher AJ, Nakamura F, Hartwig JH, Weitz DA and Stossel TP: Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin a. Nature. 478:260–263. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Yi WY, Hong W, Kang HJ, Kim HJ, Zhao W, Wang A, Seong YS and Bae I: Inhibition of the PI3K/Akt pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple-negative breast cancer cells. J Cell Mol Med. 17:648–656. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, et al: The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle. 9:1781–1791. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Xu Y, Bismar TA, Su J, Xu B, Kristiansen G, Varga Z, Teng L, Ingber DE, Mammoto A, Kumar R and Alaoui-Jamali MA: Filamin a regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion. J Exp Med. 207:2421–2437. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Uramoto H, Akyurek LM and Hanagirl T: A positive relationship between Filamin and VEGF in patiens with lung cancer. Anticancer Res. 30:3939–3944. 2010.PubMed/NCBI

44 

Park YL, Park SY, Lee SH, Kim RB, Kim JK, Rew SY, Myung DS, Cho SB, Lee WS, Kim HS and Joo YE: Filamin a interacting protein 1-like expression inhibits progression in colorectal cancer. Oncotarget. 7:72229–72241. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Sun GG, Sheng SH, Jing SW and Hu WN: An antiproliferative gene FLNA regulates migration and invasion of gastric carcinoma cell in vitro and its clinical significance. Tumor Biol. 3:2641–2648. 2014. View Article : Google Scholar

Related Articles

Journal Cover

October 2019
Volume 20 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, K., Zhu, T., & Zhao, R. (2019). Filamin A regulates EGFR/ERK/Akt signaling and affects colorectal cancer cell growth and migration. Molecular Medicine Reports, 20, 3671-3678. https://doi.org/10.3892/mmr.2019.10622
MLA
Wang, K., Zhu, T., Zhao, R."Filamin A regulates EGFR/ERK/Akt signaling and affects colorectal cancer cell growth and migration". Molecular Medicine Reports 20.4 (2019): 3671-3678.
Chicago
Wang, K., Zhu, T., Zhao, R."Filamin A regulates EGFR/ERK/Akt signaling and affects colorectal cancer cell growth and migration". Molecular Medicine Reports 20, no. 4 (2019): 3671-3678. https://doi.org/10.3892/mmr.2019.10622