Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland.
Cell Death Differ. 2017 Oct;24(10):1761-1771. doi: 10.1038/cdd.2017.81. Epub 2017 Jun 2.
Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation.
上皮分化丧失和细胞外基质（ECM）重塑已知可促进癌症进展，并与肺癌患者的预后不良相关。我们已经确定受体相互作用丝氨酸/苏氨酸蛋白激酶 4（RIP4）是肺腺癌（AC）肿瘤分化的调节剂。对人类肺 AC 样本的生物信息学分析表明，分化不良的肿瘤表达低水平的 RIP4，而高水平与更好的总生存率相关。在体外，表达低水平 RIP4 的肺肿瘤细胞显示出 STAT3 信号的增强激活，并且具有更强的穿过胶原蛋白侵袭的能力。相比之下，RIP4 的过表达抑制了 STAT3 的激活，从而阻断了白细胞介素 6 依赖性赖氨酰氧化酶的诱导，赖氨酰氧化酶是一种胶原蛋白交联酶。在 Kras（G12D）表达伴有 p53 缺失引发的肺 AC 自发小鼠模型中，Rip4 敲低肿瘤进展为低分化状态，其特征是 Hmga2 增加、Ttf1 减少以及调节细胞外重塑和 Jak-Stat 信号的基因富集。过表达 Rip4 的细胞的尾静脉注射显示出侵袭和形成肿瘤的潜力降低，这可通过共表达 Stat3 来恢复。总之，我们的工作已经确定，RIP4 的缺失增强了肺癌细胞中的 STAT3 信号，促进了 ECM 重塑基因和癌症去分化的表达。
