Integrin αvβ6 Promotes Lung Cancer Proliferation and Metastasis through Upregulation of IL-8–Mediated MAPK/ERK Signaling

Wang

et al. 2019

J Exp Clin Cancer Res

103

BackgroundInterleukin-8 (IL-8) plays a vital role in the invasion and metastasis of hepatocellular carcinoma (HCC), and is closely associated with poor prognosis of HCC patients. Integrin αvβ3, a member of the integrin family, has been reported to be overexpressed in cancer tissues and mediate the invasion and metastasis of HCC cells. However, the relationship between IL-8 and integrin αvβ3 in HCC and the underlying mechanism of IL-8 and integrin αvβ3 in the invasion of HCC remains unclear.MethodsThe expression of IL-8, integrin αv and integrin β3 in HCC cells and tissues was detected by quantitative real-time PCR, Western blot and immunohistochemistry. Transwell assay and Western blot was used to detect the invasiveness, the expression of integrin β3 and the activation of PI3K/Akt pathway of HCC cells pretreated with IL-8 knockdown or exogenous IL-8.ResultsIL-8, integrin αv and integrin β3 were overexpressed in highly metastatic HCC cell lines compared with low metastatic cell lines. There was a positive correlation between integrin β3 and IL-8 expression in HCC tissues. IL-8 siRNA transfection reduced HCC cell invasion and the levels of integrin β3, p-PI3K and p-Akt. IL-8 induced HCC cell invasion and integrin β3 expression was significantly inhibited by transfection with CXCR1 siRNA or CXCR2 siRNA. When we stimulated HCC cells with exogenous IL-8, cell invasion and the levels of integrin β3, p-PI3K, and p-Akt increased, which could be effectively reversed by adding PI3K inhibitor LY294002.ConclusionsOur results suggest that IL-8 promotes integrin β3 upregulation and the invasion of HCC cells through activation of the PI3K/Akt pathway. The IL-8/CXCR1/CXCR2/PI3K/Akt/integrin β3 axis may serve as a potential treatment target for patients with HCC.

Section: Discussionmentioning

confidence: 99%

Interleukin-8 promotes integrin β3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma

Wang

et al. 2019

J Exp Clin Cancer Res

103

“…Interleukin-8 acts as a chemoattractant for neutrophils and myeloid-derived suppressor cells and thereby contributes to the immunosuppressive nature of the tumor microenvironment. In addition, expression of IL-8 correlates with that of the αvβ6 integrin in colorectal and lung cancer disease states in which these two molecules interact to promote tumor cell proliferation and migration [37,38]. Interleukin-8 belongs to the cysteine-amino acid-cysteine (CXC) family of chemokines and, along with CXCL6, is a ligand for CXCR1.…”

Section: Introductionmentioning

confidence: 99%

CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies

Whilding

Halim

Draper

et al. 2019

Cancers

150

104

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors.

“…For example, integrin β1 is a member of the β sub-family, which forms dimers with different α subunits (α1, α2, α3, α4, α5, α6, α7, and αV). Integrin β1 (ITGB1) has vital roles in growth and motility in breast cancer, non-small cell lung cancer, gastric cancer, and liver cancer [ 16 , 17 ]. In esophageal squamous cell carcinoma (ESCC), integrin α6β1and α6β4 are preferentially located at the invasive front of tumor mass as compared to the normal epithelium, and this change is positively correlated with tumor progression [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-183-5p Inhibits Aggressiveness of Cervical Cancer Cells by Targeting Integrin Subunit Beta 1 (ITGB1)

Zhang

Liu

et al. 2018

Med Sci Monit

BackgroundAccumulating studies demonstrate that microRNAs play crucial roles in multiple processes of cancer progression. Lower levels of miR-183 have ben observed in diverse types of tumors but the mechanism and precise function of miR-183-5p in cervical cancer have largely not been investigated.Material/MethodsThe level of miR-183-5p in different cervical cancer cell lines and clinical tissues was detected qRT-PCR assays. Transwell and wound-healing migration assays were conducted to assess the functional roles of miR-183-5p in over-expressing cervical cancer cells in vitro. Rescue assays were carried out to confirm the contribution of integrin subunit Beta 1 (ITGB1) to the aggressiveness of cancer cells regulated by miR-183-5p.ResultsmiR-183-5p was reduced in clinical tissues of cervical cancer and cell lines when compared to the normal subjects and normal cervical epithelial cell line, respectively. In addition, over-expression of miR-183-5p markedly inhibited migration and invasion in cervical cancer cells, and increased aggressiveness was observed in miR-183-5p inhibitor transfected cells. Furthermore, the luciferase reporter assays revealed that ITGB1 was the gene directly regulated by miR-183-5p. Notably, a negative association between the ITGB1 and miR-183-5p was found, and the gene expressions of ITGB1 was mediated by miR-183-5p in cervical cancer cells.ConclusionsmiR-183-5p serves as a latent anti-oncogene by targeting the metastasis-promoter gene, ITGB1.