CXCR3A contributes to the invasion and metastasis of gastric cancer cells

Abstract

CXCR3, belonging to CXC chemokine receptors, has been identified to be overexpressed in various kinds of tumors. There are three mRNA variants of CXCR3 (CXCR3A, CXCR3B and CXCR3alt) in human cells. The functions of major CXCR3 isoforms (CXCR3A, CXCR3B) have been reported in some tumors including prostate and breast cancer. However, the effects of CXCR3A and CXCR3B on gastric cancer cell progression remain unknown. The present investigation found that CXCR3A mRNA level was upregulated but CXCR3B mRNA level was downregulated in gastric cancer cells and tissues. In vitro growth analysis showed that CXCR3A acted as a positive mediator in regulating cell growth, whereas CXCR3B exerted the opposite effect. In vitro invasion and migration assays showed that CXCL10 promoted gastric cancer cell invasion and migration via CXCR3A, but not CXCR3B. Moreover, knockdown of CXCR3A inhibited cell growth and metastasis in vivo. Additionally, CXCR3A knockdown attenuated matrix metalloproteinase (MMP)‑13 and IL‑6 expression, and reduced ERK1/2 activation. Together, these data suggest that CXCR3A contributes to the growth, invasion and metastasis of gastric cancer cells in vitro and in vivo, and thus may be a key mediator of gastric cancer progression.

Disparate roles of CXCR3A and CXCR3B in regulating progressive properties of colorectal cancer cells

“…CXCR3B was also able to respectively bind to its ligands CXCL10 and CXCL4 to exert their anti‐proliferative activity and anti‐migratory response, and promote necrosis in n renal cell carcinoma cells . Whereas an increased expression of CXCR3A enhanced the progressive capacity of prostate cancer cells and gastric cancer cells . In line with these findings, the results presented in this study also showed that an overexpression of CXCR3A and CXCR3B respectively increased and reduced the progressive capacities of CRC cells in term of cell proliferation, migration, and invasion, along with a decrease and an increase of cleaved‐Caspase 3 protein in CRC tumor tissues, and tumorigenicity in nude mice.…”

“…The alternative splice variants of CXCR3 exhibit differential roles in inflammations and cancers by selectively activating different signaling pathways . In this regard, CXCR3A and CXCR3B are generally considered to exert opposite functions in cancers, that is, the CXCR3A mediates signals to promote cancer cell proliferation, survival, migration and invasion, and angiostatic effects in tumors; while the CXCR3B induces signaling to suppress cancer cell growth and progression . Therefore, CXCR3 have been recognized as a prognostic marker and a therapeutic target for patients with solid tumors, including gastric cancer, prostate cancer, breast cancer, and the CRC …”

“…Compared to Lv-NC infected cells, *, **, and *** represent P < 0.05, P < 0.01, P < 0.0001, respectively variants of CXCR3 exhibit differential roles in inflammations and cancers by selectively activating different signaling pathways. 18,19,30,31 In this regard, CXCR3A and CXCR3B are generally considered to exert opposite functions in cancers, 5 that is, the CXCR3A mediates signals to promote cancer cell proliferation, survival, migration and invasion, and angiostatic effects in tumors [32][33][34] ; while the CXCR3B induces signaling to suppress cancer cell growth and progression. 14,32 Therefore, CXCR3…”

“…have been recognized as a prognostic marker and a therapeutic target for patients with solid tumors, 15 including gastric cancer, 32,35 prostate cancer, 6,34 breast cancer, 36 and the CRC. [37][38][39] Indeed, a univariate and multivariate analysis has demonstrated that that the status of CXCR3 protein was an independent prognostic marker for CRC patients, particularly in metastatic CRC.…”

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

“…[7, 8] The axis for metastases facilitates the migration of CXCR3 expressing cancer cells to ligand rich metastatic sites. As CXCR3-A plays a key role in metastasis,[51] treatment targeting only CXCR3A, not CXCR3B and CXCR3-alt, in the CXCL9, -10, -11/CXCR3 axis could be effective in metastatic disease.…”