Activation of CXCL12/CXCR4 renders colorectal cancer cells less sensitive to radiotherapy via up-regulating the expression of survivin

Wang, Dawei; Jiao, Chengbin; Zhu, Yanli; Liang, Deshen; Zao, Ming; Meng, Xiangyu; Gao, Jinpeng; He, Yunlong; Liu, Weixin; Hou, Jie; Zhong, Zhaohua; Cheng, Zhuoxin

doi:10.1177/1535370216675068

Cited by 25 publications

(22 citation statements)

References 28 publications

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“…S5). To determine the efficacy of AMD3100, we treated colorectal cancer HCT116 cells, which possess high CXCL12/CXCR4 activity (39), under the same concentration and observed reduced cell migration. In addition, we analyzed an independent RNA-seq dataset to compare CXCR4 and CXCR7 expression in 4 PCa cell lines (LNCaP, C4–2B, PC-3, and DU145), which we used in the present study (40).…”

Section: Resultsmentioning

confidence: 99%

Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Rafiei

Gui

et al. 2019

Molecular Cancer Research

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Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein-coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through activating AKT signaling pathway. Previous studies have been focused on chemokine CXCL12 and its receptor CXCR4 in mediating metastasis of various cancer types, including prostate cancer. The critical roles of CXCL12/CXCR4 axis in the interaction between cancer cells and their microenvironment render it a promising therapeutic target in cancer treatment. The data suggest that the MIF/CXCR7/AKT pathway drives CRPC growth and metastasis independent of the CXCL12/CXCR4 axis. Furthermore, CXCR7 blockade in combination with anti-androgen enzalutamide inhibits CRPC tumor growth and potentially prevents metastasis. Notably, both MIF and CXCR7 are overexpressed in CRPC patient specimens and therefore are attractive therapeutic targets for these patients. This work suggests that CXCR7 plays more important roles than CXCR4 in CRPC progression; thus, targeting CXCR7 in combination with anti-androgen is a promising therapeutic approach for metastatic CRPC.

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Section: Resultsmentioning

confidence: 99%

Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Rafiei

Gui

et al. 2019

Molecular Cancer Research

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“…In recent years, radiotherapy is known as a standard preoperative treatment approach to reduce local recurrence, exhibiting promoted apoptosis in response to radiotherapy [3]. However, CRC cells often develop the resistance to radiotherapy, which remains an intractable problem in therapeutic effect and represents a major obstacle to reduce the death of CRC cells [4]. It is reported that cancer-associated fibroblasts (CAFs), recruited from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors, is involved in therapeutic resistance in CRC cells [5].…”

Section: Introductionmentioning

confidence: 99%

Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

Chen

Liu

Zhang

et al. 2020

J Exp Clin Cancer Res

102

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Background: Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids and RNAs, all of which affect tumor microenvironment. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC). Methods: CAFs and normal fibroblasts (NFs) were isolated from cancerous tissues and matched with paracancerous tissues that had been surgically resected from CRC patients. The interaction among miR-93-5p, forkhead box A1 (FOXA1) and TGFB3 was identified through ChIP and dual luciferase reporter assays. The proliferation and apoptosis of SW480 cells co-cultured with CAFs-derived exosomes under irradiation were evaluated by CCK-8, colony formation, and flow cytometric assays. Tumorigenesis of SW480 cells in nude mice was assessed under the irradiation. Results: FOXA1 was found to be associated with reduced radioresistance in CRC cells and was verified as a target of miR-93-5p. CAFs-derived exosomes contained higher miR-93-5p than those from NFs, which augmented SW480 cell proliferation and rescued them from radiation-induced apoptosis. miR-93-5p was identified as a mediator of the exosomal effects of CAFs on SW480 cells, possibly through downregulating FOXA1 and upregulating TGFB3. FOXA1 could bind to the promoter of TGFB3, thereby inhibiting nuclear accumulation of TGFB3. Also, CAFs-derived exosomes containing miR-93-5p increased the tumor growth of SW480 cells in irradiated nude mice. Conclusion: The present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis.

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“…The present data suggested that CXCL12 served an important role in the radioresistance of cervical cancer. Recently, numerous studies demonstrated that the CXCL12/CXCR4 axis mediates resistance to radiotherapy in different cancer types (11,12). Accordingly, the function of CXCL12 was investigated to examine the mechanism of radioresistance in cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a number of studies reported that CXCL12 and CXCR4 mediate resistance to radiotherapy. Goffart et al (11) documented that CXCL12 mediates glioblastoma resistance to radiotherapy and Wang et al (12) demonstrated that CXCL12/CXCR4 serve important roles in the radioresistance of colorectal cancer cells. Therefore, CXCL12 and CXCR4 may contribute to radioresistance in a CD44-dependant manner in cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

CXCL12 modulates the radiosensitivity of cervical cancer by regulating CD44

Zhang

Luo

et al. 2018

Mol Med Report

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The aim of the present study was to investigate the regulation of stromal cell-derived factor 1 (CXCL12) in the radioresistance of cervical cancer, which was upregulated in tumors in our previous study. A CCK-8 assay was used to detect cell viability. Flow cytometry was used to measure cell apoptosis and the expression levels of CD44 and CXCR4. ELISA was performed to measure the expression level of CXCL12 protein and CXCL12 mRNA was detected by reverse transcription-quantitative polymerase chain reaction assays. Cell viability and apoptosis were determined with or without treatment with CXCL12 small interfering (si)RNA to examine the function of CXCL12 in Hela cells. The expression level of CD44 antigen (CD44) and C-X-C chemokine receptor type 4 (CXCR4) were measured using flow cytometry in the presence of CXCL12 and irradiation. In the present study, it was demonstrated that inhibition of CXCL12 reduced cell viability and increased cellular apoptosis in Hela cells treated with irradiation. Following treatment with CXCL12 siRNA, the expression level of CD44 was downregulated and the expression level of CXCR4 was upregulated. This effect of regulation additionally occurred in the presence of irradiation. In conclusion, the present data demonstrated that CXCL12 served an important role in the radioresistance of cervical cancer, suggestinh a novel therapeutic target.

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Activation of CXCL12/CXCR4 renders colorectal cancer cells less sensitive to radiotherapy via up-regulating the expression of survivin

Cited by 25 publications

References 28 publications

Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

CXCL12 modulates the radiosensitivity of cervical cancer by regulating CD44

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