Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor of the immunoglobulin superfamily. Lysophosphatidic acid (LPA) is a ligand for RAGE and is involved in physiological and pathophysiological conditions including cancer. However, RAGE-LPA axis is unexplored in lung and mammary cancer. RAGE was silenced in A549, MDA MB-231 and MCF7 using RAGE shRNA. For in vitro tumorigenesis, we performed wound healing, colony formation, cell proliferation and invasion assays. Evaluation of expression of oncogenes, EMT markers and downstream signaling molecules was done by using western blot and immunohistochemistry. For subcellular expression of RAGE, immunofluorescence was done. In vivo tumorigenesis was assessed by intraperitoneal injection of cancer cells in nude mice. Here we show RAGE mediated profound increase in proliferation, migration and invasion of lung and mammary cancer cells via LPA in Protein kinase B (PKB) dependent manner. LPA mediated EMT transition is regulated by RAGE. In vivo xenograft results show significance of RAGE in LPA mediated lung and mammary tumor progression, angiogenesis and immune cell infiltration to tumor microenvironment. Our results establish the significance and involvement of RAGE in LPA mediated lung and mammary tumor progression and EMT transition via RAGE. RAGE-LPA axis may be a therapeutic target in lung and mammary cancer treatment strategies.

中文翻译：

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溶血磷脂酸-RAGE轴通过蛋白激酶B促进肺和乳腺肿瘤发生并调节肿瘤微环境

晚期糖基化终产物受体 (RAGE) 是免疫球蛋白超家族的多配体跨膜受体。溶血磷脂酸 (LPA) 是 RAGE 的配体，参与包括癌症在内的生理和病理生理状况。然而，RAGE-LPA 轴在肺癌和乳腺癌中尚未探索。RAGE 在 A549、MDA MB-231 和 MCF7 中使用 RAGE shRNA 沉默。对于体外肿瘤发生，我们进行了伤口愈合、集落形成、细胞增殖和侵袭试验。使用蛋白质印迹和免疫组织化学对癌基因、EMT 标志物和下游信号分子的表达进行评估。对于 RAGE 的亚细胞表达，进行了免疫荧光。通过在裸鼠中腹膜内注射癌细胞来评估体内肿瘤发生。在这里，我们展示了 RAGE 通过 LPA 以蛋白激酶 B (PKB) 依赖性方式介导的肺癌和乳腺癌细胞增殖、迁移和侵袭的显着增加。LPA 介导的 EMT 转换受 RAGE 调节。体内异种移植结果显示 RAGE 在 LPA 介导的肺和乳腺肿瘤进展、血管生成和免疫细胞浸润到肿瘤微环境中的重要性。我们的结果确定了 RAGE 在 LPA 介导的肺和乳腺肿瘤进展以及通过 RAGE 的 EMT 转变中的重要性和参与。RAGE-LPA 轴可能是肺癌和乳腺癌治疗策略的治疗靶点。体内异种移植结果显示 RAGE 在 LPA 介导的肺和乳腺肿瘤进展、血管生成和免疫细胞浸润到肿瘤微环境中的重要性。我们的结果确定了 RAGE 在 LPA 介导的肺和乳腺肿瘤进展以及通过 RAGE 的 EMT 转变中的重要性和参与。RAGE-LPA 轴可能是肺癌和乳腺癌治疗策略的治疗靶点。体内异种移植结果显示 RAGE 在 LPA 介导的肺和乳腺肿瘤进展、血管生成和免疫细胞浸润到肿瘤微环境中的重要性。我们的结果确定了 RAGE 在 LPA 介导的肺和乳腺肿瘤进展以及通过 RAGE 的 EMT 转变中的重要性和参与。RAGE-LPA 轴可能是肺癌和乳腺癌治疗策略的治疗靶点。