Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis

To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized.

show abstract

“…Thus, cyclin D1 and cyclin E1 are in moderate higher activity to activate CDK4/6/2 and promote G1/S phase of cell cycle. 127 , 128 …”

Section: Ccl5/ccr5 and Diseasesmentioning

confidence: 99%

CCL5/CCR5 axis in human diseases and related treatments

et al. 2022

View full text Add to dashboard Cite

show abstract

“…miR-125a-3p harbored a negative correlation with circ_0002483 expression, repressed cell proliferation and reversed circ_0002483-induced tumor-promoting effects. In addition, CCL4-CCR5 axis contributes to breast cancer metastasis [ 36 ] and targeting CCR5 inhibits colorectal cancer liver metastasis [ 37 ]. We herein identified that CCL4 was upregulated in LUAC tissues and regarded as a direct target of miR-125a-3p.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA hsa_circ_0002483 promotes growth and invasion of lung adenocarcinoma by sponging miR-125a-3p

et al. 2021

View full text Add to dashboard Cite

Background Increasing evidence indicates that the aberrant expression of circular RNAs (circRNAs) is involved in the pathogenesis and progression of lung adenocarcinoma (LUAC). However, the function and molecular mechanisms of hsa_circ_0002483 (circ_0002483) in LUAC remain unclear. Methods The association between circ_0002483 expression and clinicopathological characteristics and prognosis in patients with LUAC was analyzed by fluorescence in situ hybridization. The functional experiments such as CCK-8, colony formation and Transwell assays and a subcutaneous tumor model were conducted to determine the role of circ_0002483 in LUAC cells. The specific binding between circ_0002483 and miR-125a-3p was validated by RNA immunoprecipitation, luciferase gene report and qRT-PCR assays. The effects of circ_0002483 on miR-125a-3p-mediated C-C motif chemokine ligand 4 (CCL4)-CCR5 axis were assessed by Western blot analysis. Results We found that circ_0002483 was upregulated in LUAC tissue samples and associated with Tumor Node Metastasis (TNM) stage and poor survival in patients with LUAC. Knockdown of circ_0002483 inhibited proliferation, colony formation and invasion of A549 and PC9 cells in vitro, whereas overexpression of circ_0002483 harbored the opposite effects. Furthermore, circ_0002483 sponged miR-125a-3p and negatively regulated its expression. CCL4 was identified as a direct target of miR-125a-3p. The rescue experiments showed that miR-125a-3p mimics reversed the tumor-promoting effects of circ_0002483 by targeting CCL4-CCR5 axis in A549 and PC9 cells. In addition, the in vivo experiment further validated that knockdown of circ_0002483 repressed tumor growth. Conclusions Our findings demonstrated that circ_0002483 could act as a sponge of miR-125a-3p to upregulate CCL4-CCR5 axis, contributing to the tumorigenesis of LUAC, and represent a potential therapeutic target for LUAC.

show abstract

“…In fact, several reports associate CCR5/CCL5 intermediate or strong expression to extended CRC patient survival as well as tumor regression [31,32], but other studies show that this chemokine receptor significantly contributes to tumor growth through its main actors CCL5, CCL4 and CCL3 [11,16,19,29], and that neutralization of this receptor's chemokines can reduce tumor invasion in colorectal [21,23], breast [33,34] and lung cancers [35,36]. For CRC treatment, CCR5 is widely studied, given its involvement in cancer progression and metastasis, and is a frequently inhibited using specific molecules to hinder the interaction between mesenchymal stem cells (MSC)/CRC cells and to effectively treat CRC advanced stages [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies similar to ours and in different cancer types (colorectal, breast, lung) have demonstrated that overexpression of a functional CCR5 is heavily involved in chemotaxis and immune cells' recruitment to the tumor dissemination site, highlighting a chemokine-receptors protumor effect [22,53]. They demonstrate through in vitro or in vivo experiments that targeting CCR5 via siRNA (second RNA interference) or an FDA (Food and Drug Administration)-approved antagonist (maraviroc), hinders the receptor's biological activity and can be an effective therapy for treating CRC and liver metastasis [21,23,38]. The chemokine-receptor complex molecular interactions seem to be in favor of the immune system and consequently tumor cell elimination [30,31], but CCL5 [16,23], CCL3 [10,15,29] and CCL4 [11,14,15] overexpression, by different cells as well as tumors cells in the tumor microenvironment, exhibit protumor properties [30].…”

Section: Discussionmentioning

confidence: 99%

The role of CCR5 polymorphism in colorectal cancer and liver metastasis in the Tunisian population

Weslati

Ounissi

Hazgui

et al. 2021

ARCH BIOL SCI BELGRA

View full text Add to dashboard Cite

Chemokines and their receptors are involved in cancer initiation and progression, including colorectal cancer (CRC) and liver metastasis formation. Our aim was to elucidate C-C chemokine receptor type 5 (CCR5) gene polymorphism (CCR5?32) impact on CRC and colorectal cancer liver metastases (CRLM) occurrence risk. We analyzed the CCR5 gene mutational status in 108 primary CRC cases, 35 CRLM and 248 healthy individuals, and evaluated CCR5 expression in healthy tissue and tumors. Rare allele ??32? was more frequent in controls (7.2% vs 2.8% in CRC). All 35 metastases had wild-type CCR5. Our analysis showed that CCR5 wild type has a significant risk of 2.73-fold (95% CI=1.22-7.31) to cause CRC while ?32 reduced the risks 0.36-fold (95% CI=0.13-0.82). For CRC, CCR5 correlated with left-sided tumors and liver metastases (P=0.040 and P= 0.039 respectively). As for CRLM, no correlation was found. Immunohistochemical profile analysis of CCR5 revealed a significant association with the male gender (P=0.049) and non-mucinous carcinomas (P< 0.001) in primary CRC. CCR5 expression revealed an association with the degree of tumor differentiation for both CRC and CRLM (P < 0.001). CCR5?32 might be a protective factor against CRC development and dissemination.

show abstract

Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis

Cited by 26 publications

References 63 publications

CCL5/CCR5 axis in human diseases and related treatments

CCL5/CCR5 axis in human diseases and related treatments

Circular RNA hsa_circ_0002483 promotes growth and invasion of lung adenocarcinoma by sponging miR-125a-3p

The role of CCR5 polymorphism in colorectal cancer and liver metastasis in the Tunisian population

Contact Info

Product

Resources

About