The IL6 family of cytokines, including IL6 and leukemia-inhibitory factor (LIF), are induced during inflammation and are also expressed in many types of cancer where they play an important role in tumor development. IL6 family cytokines mainly activate the JAK–STAT3 pathway via the coreceptor, gp130, and IL6 is known to activate the Src family kinase (SFK)–Yes-associated protein (YAP) pathway. The current study investigated the role of autocrine LIF in human esophageal squamous cell carcinoma (ESCC) that highly expresses LIF. LIF knockdown had various effects on cancer cells, including profound changes in gene expression, suppression of cell proliferation, migration/invasion and sphere formation, and induction of apoptosis. Similar to IL6, LIF activated the SFK–YAP pathway as well as the JAK–STAT3 pathway. LIF-induced YAP activation was more important for cancer cell proliferation than LIF-induced STAT3 activation, and concomitant YAP and STAT3 activation completely compensated for the role of LIF in human ESCC growth. We also confirmed that SFK activation and LIF expression were correlated with YAP activation in human ESCC clinical samples. Furthermore, simultaneous inhibition of the SFK–YAP and JAK–STAT3 pathways in human ESCC cells was more effective at suppressing cell proliferation than single inhibition, and autocrine LIF signaling promoted human ESCC growth in vivo. Therefore, the LIF–SFK–YAP axis may represent a new therapeutic target for human ESCC. Implications: Autocrine LIF signaling promotes human ESCC progression via SFK-dependent YAP activation and is a new potential target of treatment for human ESCC.

中文翻译：

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自分泌白血病抑制因子通过 Src 家族激酶依赖性 Yes 相关蛋白激活促进食管鳞状细胞癌进展

IL6 细胞因子家族，包括 IL6 和白血病抑制因子 (LIF)，在炎症过程中被诱导，并且也在许多类型的癌症中表达，它们在肿瘤发展中发挥重要作用。IL6 家族细胞因子主要通过辅助受体 gp130 激活 JAK-STAT3 通路，已知 IL6 可激活 Src 家族激酶 (SFK)-Yes 相关蛋白 (YAP) 通路。目前的研究调查了自分泌 LIF 在高表达 LIF 的人食管鳞状细胞癌 (ESCC) 中的作用。LIF 敲低对癌细胞有多种影响，包括基因表达的深刻变化、细胞增殖、迁移/侵袭和球体形成的抑制，以及细胞凋亡的诱导。与 IL6 类似，LIF 激活 SFK-YAP 通路以及 JAK-STAT3 通路。LIF 诱导的 YAP 激活对癌细胞增殖比 LIF 诱导的 STAT3 激活更重要，并且伴随的 YAP 和 STAT3 激活完全补偿了 LIF 在人类 ESCC 生长中的作用。我们还证实，SFK 激活和 LIF 表达与人类 ESCC 临床样本中的 YAP 激活相关。此外，在人 ESCC 细胞中同时抑制 SFK-YAP 和 JAK-STAT3 通路在抑制细胞增殖方面比单一抑制更有效，并且自分泌 LIF 信号在体内促进人 ESCC 生长。因此，LIF-SFK-YAP 轴可能代表人类 ESCC 的新治疗靶点。意义：自分泌 LIF 信号通过 SFK 依赖性 YAP 激活促进人类 ESCC 进展，并且是人类 ESCC 治疗的新潜在目标。