RAGE acts as an oncogenic role and promotes the metastasis of human lung cancer

Abstract

RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21 CIP1 expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21 CIP1 up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.

Research trends in pharmacological modulation of tumor‐associated macrophages

“…RAGE (receptor for advanced glycation end‐product) is a member of the immunoglobulin superfamily and has been reported to be highly expressed on the surface of macrophages 159 . It has been reported that RAGE overexpression could induce the accumulation of TAMs and thus accelerate the growth of lung cancer xenografts in vivo 160 . Mechanistically, RAGE expression strictly correlates to the metabolic switch in cancer and immune cells.…”

“…On one hand, the formation of AGEs could impair the phagocytosis function of M1‐like macrophages within the TME 162 . On the other hand, AGEs could induce RAGE expression in macrophages and their interaction could further promote cancer progression and metastasis by recruiting TAMs 160,163 . Therefore, AGEs/RAGE signaling may also represent a metabolism‐related target for the pharmacological modulation of TAMs, which still needs further investigations.…”

“…159 It has been reported that RAGE overexpression could induce the accumulation of TAMs and thus accelerate the growth of lung cancer xenografts in vivo. 160 Mechanistically, RAGE expression strictly correlates to the metabolic switch in cancer and immune cells. For example, cancer cells usually exhibit a metabolism switch characterized by decreased mitochondrial oxidative phosphorylation as well as elevated glycolysis, leading to the overproduction of toxic glucose metabolites.…”

Thymosin β10 promotes tumor-associated macrophages M2 conversion and proliferation via the PI3K/Akt pathway in lung adenocarcinoma

“…Immunohistochemistry. Immunohistochemical assay was performed on the 5 mm thick slides, using mouse anti-human TMSB10 (1:500, Sant cruz, sc-514309) and CD68 (1:1000, CST, 76437) primary antibody, as previously (23). Two experienced investigators independently scored the TAMs-associated TMSB10 without knowing the clinical data.…”

Thymosin β10 promotes tumor-associated macrophages M2 conversion and proliferation via the PI3K/Akt pathway in lung adenocarcinoma

“…Immunohistochemistry. Immunohistochemical assay was performed on the 5 mm thick slides, using mouse anti-human TMSB10 (1:500, Sant cruz, sc-514309) and CD68 (1:1000, CST, 76437) primary antibody, as previously (22). Two experienced investigator independently scored the TAMs-associated TMSB10 without knew the clinical data.…”