CXCR4 uses STAT3-mediated slug expression to maintain radioresistance of non-small cell lung cancer cells: emerges as a potential prognostic biomarker for lung cancer

Abstract

Lung cancer is one of the most common reasons for cancer-induced mortality across the globe, despite major advancements in the treatment strategies including radiotherapy and chemotherapy. Existing reports suggest that CXCR4 is frequently expressed by malignant tumor and is imperative for vascularization, tumor growth, cell migration, and metastasis pertaining to poor prognosis. In this study, we infer that CXCR4 confers resistance to ionizing radiation (IR) in nonsmall cell lung cancer (NSCLC) cells. Further, on the basis of colony forming ability, one finds that drug-resistant A549/GR cells with improved CXCR4 expression exhibited more resistance to IR than A549 cells evidenced along with a reduction in the formation of γ-H2AX foci after IR. Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR. Conversely, the overexpression of CXCR4 in A549 and H460 cell lines was found to improve clonogenic survival, and reduce the formation of γ-H2AX foci after IR. CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.

Inhibiting p21-activated kinase (PAK7) enhances radiosensitivity in hepatocellular carcinoma

“…During the DSB resulted from various factors, H2AX is phosphorylated into g-H2AX, which, thus, has been taken as an indicator for DNA damage and repair, and its upregulation indicated the exacerbation of DNA damage. 40,41 In our study, we found that the knockout of PAK7 in HCC cells could further increase the IR-induced expression of g-H2AX, which could indirectly implied that PAK7 might reduce the DSB of DNA in HCC cells and accelerate the repair of DNA damage, thereby weakening the sensitivity of cells to radiotherapy. Irradiationassociated DNA damage can lead to G2/M checkpoint activation and consequent G2/M phase arrest, enabling DNA repair to occur prior to cellular entry into mitosis.…”

Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer

“…We previously demonstrated an association between CXCL12/CXCR4 signaling and gemcitabine resistance in gemcitabine-resistant PaCa cell lines ( 32 ). In addition, CXCR4 may be involved in radiation resistance in colorectal cancer ( 50 ), thyroid cancer ( 51 ), and non-small cell lung cancer ( 52 ). We established radiation-resistant PaCa cell lines to investigate the factors involved in the radiation resistance of PaCa.…”

Developing ZNF Gene Signatures Predicting Radiosensitivity of Patients with Breast Cancer

“…STAT3 is a central regulator of tumor immune tolerance. Importantly, STAT3 can act as a negative feedback regulator, and targeted inhibition of STAT3 can enhance the efficacy of radiotherapy for head and neck cancer [ 48 ], lung cancer [ 49 ], and breast cancer [ 50 ]. Studies have shown that transcription factor ZNF341 is a positive regulator of STAT3 expression [ 51 ].…”