Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Sam68 Promotes the Progression of Human Breast Cancer through inducing Activation of EphA3

Author(s): Xinxin Chen*, Lehong Zhang*, Min Yuan, Ziqiao Kuang, Ying Zou, Tian Tang, Wangjian Zhang, Xiaowu Hu, Ting Xia , Tengfei Cao and Haixia Jia

Volume 20, Issue 1, 2020

Page: [76 - 83] Pages: 8

DOI: 10.2174/1568009619666190718124541

Price: $65


Background: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer.

Materials and Methods: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68.

Results: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer.

Conclusion: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.

Keywords: Sam68, breast cancer, EPHA3, metastasis, immunohistochemistry, Xenograft.

« Previous
Graphical Abstract
Nathanson, S.D.; Krag, D.; Kuerer, H.M.; Newman, L.A.; Brown, M.; Kerjaschki, D.; Pereira, E.R.; Padera, T.P. Breast cancer metastasis through the lympho-vascular system. Clin. Exp. Metastasis, 2018, 35(5-6), 443-454.
[] [PMID: 29796854]
Huot, M.E.; Brown, C.M.; Lamarche-Vane, N.; Richard, S. An adaptor role for cytoplasmic Sam68 in modulating Src activity during cell polarization. Mol. Cell. Biol., 2009, 29(7), 1933-1943.
[] [PMID: 19139276]
Richard, S.; Vogel, G.; Huot, M.E.; Guo, T.; Muller, W.J.; Lukong, K.E. Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis. Oncogene, 2008, 27(4), 548-556.
[] [PMID: 17621265]
Wang, L.; Cui, Y.; Liao, W.; Liu, S. Role of Sam68 in proliferation, invasion and migration of colorectal cancer cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao, 2014, 34(4), 546-551.
[PMID: 24752106]
Zhang, Z.; Yu, C.; Li, Y.; Jiang, L.; Zhou, F. Utility of SAM68 in the progression and prognosis for bladder cancer. BMC Cancer, 2015, 15, 364.
[] [PMID: 25944080]
Janes, P.W.; Slape, C.I.; Farnsworth, R.H.; Atapattu, L.; Scott, A.M.; Vail, M.E. EphA3 biology and cancer. Growth Factors, 2014, 32(6), 176-189.
[] [PMID: 25391995]
Chiari, R.; Hames, G.; Stroobant, V.; Texier, C.; Maillère, B.; Boon, T.; Coulie, P.G. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res., 2000, 60(17), 4855-4863.
[PMID: 10987298]
Bielli, P.; Busà, R.; Paronetto, M.P. Sette, C. The RNA-binding protein Sam68 is a multifunctional player in human cancer. Endocr. Relat. Cancer, 2011, 18(4), R91-R102.
[] [PMID: 21565971]
Taylor, S.J.; Resnick, R.J.; Shalloway, D. Sam68 exerts separable effects on cell cycle progression and apoptosis. BMC Cell Biol., 2004, 5, 5.
[] [PMID: 14736338]
Zhang, Z.; Li, J.; Zheng, H.; Yu, C.; Chen, J.; Liu, Z.; Li, M.; Zeng, M.; Zhou, F.; Song, L. Expression and cytoplasmic localization of SAM68 is a significant and independent prognostic marker for renal cell carcinoma. Cancer Epidemiol. Biomarkers Prev., 2009, 18(10), 2685-2693.
[] [PMID: 19755649]
Li, Z.; Yu, C.P.; Zhong, Y.; Liu, T.J.; Huang, Q.D.; Zhao, X.H.; Huang, H.; Tu, H.; Jiang, S.; Zhang, Y.; Liu, J.H.; Song, L.B. Sam68 expression and cytoplasmic localization is correlated with lymph node metastasis as well as prognosis in patients with early-stage cervical cancer. Ann. Oncol., 2012, 23(3), 638-646.
[] [PMID: 21700735]
Dumbovic, G.; Biayna, J.; Banús, J.; Samuelsson, J.; Roth, A.; Diederichs, S.; Alonso, S.; Buschbeck, M.; Perucho, M.; Forcales, S.V. A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer. Nucleic Acids Res., 2018, 46(11), 5504-5524.
[] [PMID: 29912433]
Yim, S.Y.; Shim, J.J.; Shin, J.H.; Jeong, Y.S.; Kang, S.H.; Kim, S.B.; Eun, Y.G.; Lee, D.J.; Conner, E.A.; Factor, V.M.; Moore, D.D.; Johnson, R.L.; Thorgeirsson, S.S.; Lee, J.S. Integrated genomic comparison of mouse models reveals their clinical resemblance to human liver cancer. Mol. Cancer Res., 2018.
Romano, G.; Chagani, S.; Kwong, L.N. The path to metastatic mouse models of colorectal cancer. Oncogene, 2018, 37(19), 2481-2489.
[] [PMID: 29463860]
Mendes, O.; Kim, H.T.; Stoica, G. Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin. Exp. Metastasis, 2005, 22(3), 237-246.
[] [PMID: 16158251]
Kalhori, V.; Törnquist, K. MMP2 and MMP9 participate in S1P-induced invasion of follicular ML-1 thyroid cancer cells. Mol. Cell. Endocrinol., 2015, 404, 113-122.
[] [PMID: 25643979]
Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010, 141(1), 52-67.
[] [PMID: 20371345]
Limoge, M.; Safina, A.; Beattie, A.; Kapus, L.; Truskinovsky, A.M.; Bakin, A.V. Tumor-fibroblast interactions stimulate tumor vascularization by enhancing cytokine-driven production of MMP9 by tumor cells. Oncotarget, 2017, 8(22), 35592-35608.
[] [PMID: 28423685]
Canavese, M.; Dottorini, T.; Crisanti, A. VEGF and LPS synergistically silence inflammatory response to Plasmodium berghei infection and protect against cerebral malaria. Pathog. Glob. Health, 2015, 109(6), 255-265.
[] [PMID: 26392042]
Adams, J.; Carder, P.J.; Downey, S.; Forbes, M.A.; MacLennan, K.; Allgar, V.; Kaufman, S.; Hallam, S.; Bicknell, R.; Walker, J.J.; Cairnduff, F.; Selby, P.J.; Perren, T.J.; Lansdown, M.; Banks, R.E. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res., 2000, 60(11), 2898-2905.
[PMID: 10850435]
Rezaei, M.; Hashemi, M.; Sanaei, S.; Mashhadi, M.A.; Taheri, M. Association between vascular endothelial growth factor gene polymorphisms with breast cancer risk in an Iranian population. Breast Cancer (Auckl.), 2016, 10, 85-91.
[] [PMID: 27398026]
Lu, Y.; Xu, Q.; Zuo, Y.; Liu, L.; Liu, S.; Chen, L.; Wang, K.; Lei, Y.; Zhao, X.; Li, Y. Isoprenaline/β2-AR activates Plexin-A1/VEGFR2 signals via VEGF secretion in gastric cancer cells to promote tumor angiogenesis. BMC Cancer, 2017, 17(1), 875.
[] [PMID: 29262812]
Santamaria, P.G.; Moreno-Bueno, G.; Portillo, F.; Cano, A. EMT: Present and future in clinical oncology. Mol. Oncol., 2017, 11(7), 718-738.
[] [PMID: 28590039]
Polyak, K.; Weinberg, R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer, 2009, 9(4), 265-273.
[] [PMID: 19262571]
Nasri, B.; Inokuchi, M.; Ishikawa, T.; Uetake, H.; Takagi, Y.; Otsuki, S.; Kojima, K.; Kawano, T. High expression of EphA3 (erythropoietin-producing hepatocellular A3) in gastric cancer is associated with metastasis and poor survival. BMC Clin. Pathol., 2017, 17, 8.
[] [PMID: 28465671]
Andretta, E.; Cartón-García, F.; Martínez-Barriocanal, Á.; de Marcondes, P.G.; Jimenez-Flores, L.M.; Macaya, I.; Bazzocco, S.; Bilic, J.; Rodrigues, P.; Nieto, R.; Landolfi, S.; Ramon, Y. Cajal, S.; Schwartz, S.; Brown, A.; Dopeso, H.; Arango, D. Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer. Sci. Rep., 2017, 7, 41576.
[] [PMID: 28169277]
Vail, M.E.; Murone, C.; Tan, A.; Hii, L.; Abebe, D.; Janes, P.W.; Lee, F.T.; Baer, M.; Palath, V.; Bebbington, C.; Yarranton, G.; Llerena, C.; Garic, S.; Abramson, D.; Cartwright, G.; Scott, A.M.; Lackmann, M. Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment. Cancer Res., 2014, 74(16), 4470-4481.
[] [PMID: 25125683]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy