Home Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer
Article
Licensed
Unlicensed Requires Authentication

Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer

  • Ling-li Zhang , Lian-feng Zhang and Yun-bo Shi EMAIL logo
Published/Copyright: June 20, 2018

Abstract

The paxillin and M2 macrophage are all involved in cell proliferation and tumor progression, and this study aims to explore the interaction between them in colon cancer and the role of paxillin in cancer progression. Expression of mRNAs and proteins was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, separately. Endogenous expression of genes was modulated by recombinant plasmids and cell transfection. The levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The cell viability, invasion and migration were detected using the MTT assay, the transwell assay and the wound-healing cell migration assay, respectively. A nude mouse model for human colon cancer was constructed for tumor orthotopic expression. Paxillin was up-regulated in tumor-associated macrophages (TAMs). Paxillin was up-regulated in process of M2 macrophage polarization. M2 macrophage polarization was inhibited with paxillin suppressed. Down-regulated paxillin inhibited cell proliferation and invasion in colon cancer through suppressing M2 macrophage polarization. PI3k/Akt inhibitor repressed M2 macrophage polarization through down-regulating paxillin. PI3k/Akt inhibitor inhibited the function of the macrophage in promoting cell proliferation and invasion of colon cancer through down-regulating paxillin. Down-regulated paxillin in macrophages inhibited tumor growth of colon cancer. With the PI3K/AKT pathway inhibited, down-regulated paxillin suppressed colon cancer cell proliferation and invasion by inhibiting the M2 macrophage polarization, thereby restraining the tumor progression.

  1. Conflict of interest statement: The authors declare that they have no conflict of interest.

References

Abshire, M.Y., Thomas, K.S., Owen, K.A., and Bouton, A.H. (2011). Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events. J. Leukoc. Biol. 89, 251–257.10.1189/jlb.0710395Search in Google Scholar PubMed PubMed Central

Ameka, M., Kahle, M.P., Perez-Neut, M., Gentile, S., Mirza, A.A., and Cuevas, B.D. (2014). MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells. Biochem. J. 464, 99–108.10.1042/BJ20140420Search in Google Scholar PubMed PubMed Central

Birt, D.F. and Phillips, G.J. (2014). Diet, genes, and microbes: complexities of colon cancer prevention. Toxicol. Pathol. 42, 182–188.10.1177/0192623313506791Search in Google Scholar PubMed PubMed Central

Chen, Y., Wang, S.X., Mu, R., Luo, X., Liu, Z.S., Liang, B., Zhuo, H.L., Hao, X.P., Wang, Q., Fang, D.F., et al. (2014). Dysregulation of the miR-324-5p-CUEDC2 axis leads to macrophage dysfunction and is associated with colon cancer. Cell Rep. 7, 1982–1993.10.1016/j.celrep.2014.05.007Search in Google Scholar PubMed

Deakin, N.O. and Turner, C.E. (2008). Paxillin comes of age. J. Cell Sci. 121, 2435–2444.10.1242/jcs.018044Search in Google Scholar PubMed PubMed Central

Du, C., Wang, X., Zhang, J., Liu, X., Zhu, J., and Liu, Y. (2016). Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of paxillin improves sensitivity to cetuximab in colorectal cancer cells. Oncol. Rep. 35, 409–417.10.3892/or.2015.4352Search in Google Scholar PubMed

Fearon, E.R. (2011). Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 6, 479–507.10.1146/annurev-pathol-011110-130235Search in Google Scholar PubMed

Guo, H., German, P., Bai, S., Barnes, S., Guo, W., Qi, X., Lou, H., Liang, J., Jonasch, E., Mills, G.B., et al. (2015). The PI3K/AKT pathway and renal cell carcinoma. J. Genet. Genomics 42, 343–353.10.1016/j.jgg.2015.03.003Search in Google Scholar PubMed PubMed Central

Huang, C.C., Wu, D.W., Lin, P.L., and Lee, H. (2015). Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at serine 87. Oncotarget 6, 8698–8708.10.18632/oncotarget.3537Search in Google Scholar PubMed PubMed Central

Jiang, X., Zhou, T., Xiao, Y., Yu, J., Dou, S., Chen, G., Wang, R., Xiao, H., Hou, C., Wang, W., et al. (2016). Tim-3 promotes tumor-promoting M2 macrophage polarization by binding to STAT1 and suppressing the STAT1-miR-155 signaling axis. Oncoimmunology 5, e1211219.10.1080/2162402X.2016.1211219Search in Google Scholar PubMed PubMed Central

Kawada, I., Hasina, R., Lennon, F.E., Bindokas, V.P., Usatyuk, P., Tan, Y.H., Krishnaswamy, S., Arif, Q., Carey, G., Hseu, R.D., et al. (2013). Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: relevance to lung cancer. Cancer Biol. Ther. 14, 679–691.10.4161/cbt.25091Search in Google Scholar

Lee, M., Park, J.J., and Lee, Y.S. (2010). Adhesion of ST6Gal I-mediated human colon cancer cells to fibronectin contributes to cell survival by integrin beta1-mediated paxillin and AKT activation. Oncol. Rep. 23, 757–761.Search in Google Scholar

Liu, C.Y., Xu, J.Y., Shi, X.Y., Huang, W., Ruan, T.Y., Xie, P., and Ding, J.L. (2013). M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab. Invest. 93, 844–854.10.1038/labinvest.2013.69Search in Google Scholar

Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555.10.1016/S1471-4906(02)02302-5Search in Google Scholar

Martini, M., De Santis, M.C., Braccini, L., Gulluni, F., and Hirsch, E. (2014). PI3K/AKT signaling pathway and cancer: an updated review. Ann. Med. 46, 372–383.10.3109/07853890.2014.912836Search in Google Scholar PubMed

Meng, Z., Cao, R., Yang, Z., Liu, T., Wang, Y., and Wang, X. (2013). Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin. Urology 82, 1452.e7–1452e.14.10.1016/j.urology.2013.08.060Search in Google Scholar PubMed

Mia, S., Warnecke, A., Zhang, X.M., Malmstrom, V., and Harris, R.A. (2014). An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF-β yields a dominant immunosuppressive phenotype. Scand. J. Immunol. 79, 305–314.10.1111/sji.12162Search in Google Scholar PubMed PubMed Central

Reinartz, S., Schumann, T., Finkernagel, F., Wortmann, A., Jansen, J.M., Meissner, W., Krause, M., Schworer, A.M., Wagner, U., Muller-Brusselbach, S., et al. (2014). Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int. J. Cancer 134, 32–42.10.1002/ijc.28335Search in Google Scholar PubMed PubMed Central

Schaller, M.D. (2001). Paxillin: a focal adhesion-associated adaptor protein. Oncogene 20, 6459–6472.10.1038/sj.onc.1204786Search in Google Scholar PubMed

St-Pierre, J. and Ostergaard, H.L. (2013). A role for the protein tyrosine phosphatase CD45 in macrophage adhesion through the regulation of paxillin degradation. PLoS One 8, e71531.10.1371/journal.pone.0071531Search in Google Scholar PubMed PubMed Central

Tamas, K., Walenkamp, A.M., de Vries, E.G., van Vugt, M.A., Beets-Tan, R.G., van Etten, B., de Groot, D.J., and Hospers, G.A. (2015). Rectal and colon cancer: not just a different anatomic site. Cancer Treat. Rev. 41, 671–679.10.1016/j.ctrv.2015.06.007Search in Google Scholar PubMed

Xu, L., Yang, F., Lin, R., Han, C., Liu, J., and Ding, Z. (2014). Induction of m2 polarization in primary culture liver macrophages from rats with acute pancreatitis. PLoS One 9, e108014.10.1371/journal.pone.0108014Search in Google Scholar PubMed PubMed Central

Yamaguchi, T., Fushida, S., Yamamoto, Y., Tsukada, T., Kinoshita, J., Oyama, K., Miyashita, T., Tajima, H., Ninomiya, I., Munesue, S., et al. (2016). Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. Gastric Cancer 19, 1052–1065.10.1007/s10120-015-0579-8Search in Google Scholar PubMed PubMed Central

Yang, M., Liu, J., Piao, C., Shao, J., and Du, J. (2015). ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis. Cell Death Dis. 6, e1780.10.1038/cddis.2015.144Search in Google Scholar PubMed PubMed Central

Yeung, O.W., Lo, C.M., Ling, C.C., Qi, X., Geng, W., Li, C.X., Ng, K.T., Forbes, S.J., Guan, X.Y., Poon, R.T., et al. (2015). Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 62, 607–616.10.1016/j.jhep.2014.10.029Search in Google Scholar PubMed

Yin, H., Zhang, Q., Wang, X., Li, T., Wan, Y., Liu, Y., and Zhu, J. (2014). Role of paxillin in colorectal carcinoma and its relationship to clinicopathological features. Chin. Med. J. (Engl.). 127, 423–429.Search in Google Scholar

Zhang, Y., Sime, W., Juhas, M., and Sjolander, A. (2013). Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. Eur. J. Cancer. 49, 3320–3334.10.1016/j.ejca.2013.06.005Search in Google Scholar PubMed

Zhang, L.L., Mu, G.G., Ding, Q.S., Li, Y.X., Shi, Y.B., Dai, J.F., and Yu, H.G. (2015). Phosphatase and Tensin Homolog (PTEN) represses colon cancer progression through inhibiting paxillin transcription via PI3K/AKT/NF-κB pathway. J. Biol. Chem. 290, 15018–15029.10.1074/jbc.M115.641407Search in Google Scholar PubMed PubMed Central

Zhang, W., Chen, L., Ma, K., Zhao, Y., Liu, X., Wang, Y., Liu, M., Liang, S., Zhu, H., and Xu, N. (2016). Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells. Oncotarget 7, 75366–75378.10.18632/oncotarget.12207Search in Google Scholar PubMed PubMed Central

Received: 2018-01-02
Accepted: 2018-06-08
Published Online: 2018-06-20
Published in Print: 2018-10-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 6.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0002/pdf
Scroll to top button