The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan-in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF-1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF-1α are highly co-expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF-1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF-1α expression, whereas ectopic RON expression in RON null cells induced HIF-1α expression suggesting the direct regulation of HIF-1α by RON kinase receptor. RON regulates HIF-1α through an unreported transcriptional mechanism involving PI3 kinase-mediated AKT phosphorylation and Sp1-dependent HIF-1α promoter activity leading to increased HIF-1α mRNA expression. RON/HIF-1α modulation altered the invasive behavior of PDAC cells. A small-molecule RON kinase inhibitor decreased RON ligand, MSP-induced HIF-1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF-1α expression. RON/HIF-1α co-expression also exists in triple-negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF-1α axis in any tumor type and is a potential novel therapeutic target.

中文翻译：

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RON激酶受体与胰腺癌缺氧诱导因子1α之间的潜在信号轴

胰腺癌队列的癌症基因组图谱 (TCGA) 确定了与人类胰腺癌预后不良相关的高 MST1R（RON 酪氨酸激酶受体）表达。RON 表达在正常胰腺中是无效的/最小的，但从泛入病变通过浸润性癌升高。我们报告了使用多种方法 RON 直接调节 HIF-1 α，这是参与癌细胞侵袭和转移的基因的关键驱动因素。RON 和 HIF-1 α在分析的 101 个人类 PDAC 肿瘤中高度共表达，并且 RON 表达与PDAC 细胞系子集中的HIF-1 α表达相关。RON 阳性细胞中 RON 表达的敲低阻断 HIF-1 α表达，而 RON 无效细胞中的异位 RON 表达诱导 HIF-1α表达表明RON 激酶受体对 HIF-1 α的直接调节。RON 通过一种未报道的转录机制调节 HIF-1 α，该机制涉及 PI3 激酶介导的 AKT 磷酸化和 Sp1 依赖性 HIF-1 α启动子活性，导致 HIF-1 α mRNA 表达增加。RON/HIF-1 α调制改变了 PDAC 细胞的侵袭行为。一种小分子 RON 激酶抑制剂降低了 RON 配体、MSP 诱导的 HIF-1 α表达和 PDAC 细胞的侵袭。对 RON 敲低原位 PDAC 肿瘤异种移植物的免疫组织化学分析证实，RON 抑制显着阻断了 HIF-1 α表达。RON/HIF- 1α三阴性乳腺癌细胞中也存在共表达，这种肿瘤类型也缺乏分子治疗靶点。这是第一份描述任何肿瘤类型中 RON/HIF-1 α轴的报告，是一种潜在的新型治疗靶点。