Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR–Hippo–YAP pathway

Abstract

The long‐term outcome of gastric cancer (GC) patients remains unsatisfactory despite some recent improvements. Leukemia inhibitory factor (LIF) is a prognostic biomarker for some solid tumors, however its role in GC remains unknown. In this study, we demonstrated that LIF and LIF receptor (LIFR) are overexpressed in GC tissues and established that a correlation exists between them. LIF and LIFR expression are associated with tumor differentiation, lymphovascular invasion, tumor stage, lymph node metastasis, and pTNM stage, indicating that they may be useful prognostic factors. LIF promoted GC cell proliferation, colony formation, invasion, migration, and tumor growth; it also promoted cell cycle progression and inhibited apoptosis; and knocking out the LIFR gene reversed the effects of LIF. LIF inhibited the activity of the Hippo pathway, resulting in reduced phosphorylation of YAP, increased YAP nuclear translocation, and increased cell proliferation. Finally, silencing YAP mRNA expression suppressed cell proliferation. Overall, the results demonstrate that LIF promotes the malignant biological behavior of GC cells through LIFR–Hippo–YAP signaling. LIF may therefore be a useful biomarker for GC.

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

“…Other studies have also associated LIF signalling with EMP features such as increased cell migration, invasion, CSC properties and metastasis, reporting both promoting and inhibitory roles, despite not always showing a direct link between LIF and EMP. In gastric cancer, LIF promoted proliferation, colony formation, invasion, migration and tumour growth by inhibiting the Hippo pathway, resulting in increased YAP nuclear translocation and transcriptional activity, giving rise to cancer cells with decreased E-cadherin and increased MMP7 protein levels [ 104 ]. Interestingly, LIF promoted mesenchymal epithelial transition in lung cancer cells through the LIF/LIFR/p-ERK/pS727-STAT3 signalling pathway leading to increased metastasis [ 42 ].…”

Hsa_circ_0001073 targets miR‐626/LIFR axis to inhibit lung cancer progression

“…Zhang et al suggested that LIFR promoted prostate cancer tumorigenesis and metastasis 34 . Bian et al reported that LIF/LIFR promoted the malignant biological behavior of gastric cancer cells by Hippo/Yes‐associated protein signaling 35 . However, whether LIFR is responsible for circ_0011780/miR‐626 axis in lung cancer progression is uncertain.…”

Emerging Perspectives on Leukemia Inhibitory Factor and its Receptor in Cancer

“…Although the precise reasons may differ among cancers, few have made significant forays into the underlying molecular mechanisms by which LIFRβ plays a role as a metastasis and tumorigenic suppressor. The most relevant underlying molecular mechanisms demonstrated have defined connections to the tumor suppressor Hippo pathway, and links between LIFRβ and the Hippo pathway have been demonstrated in breast ( 59 ), clear renal cell carcinoma ( 64 ), and gastric cancer ( 93 ). Although LIF-LIFR signaling activates a variety of pathways associated with cancer progression such as JAK/STAT and MAPK, more potent and significant activators of these pathways already exist and are potential targets for treatment.…”

“…Additionally, a study of gastric cancer found that higher levels of LIF and LIFR were associated with increased proliferation, invasion, and metastasis ( 93 ). Interestingly they determined that LIF-LIFR signaling actually inhibited Scribble localization to cell membranes, thereby preventing the inactivation of YAP through the Hippo pathway.…”

“…Interestingly they determined that LIF-LIFR signaling actually inhibited Scribble localization to cell membranes, thereby preventing the inactivation of YAP through the Hippo pathway. When YAP was inhibited via shRNA, the effect of LIF-LIFR signaling on cancer growth and migration was lost ( 93 ). In a dose dependent manner, LIF decreased the phosphorylation of MST and LATS, implying that LIF-LIFR signaling is somehow inhibiting the Hippo pathway and allowing YAP to remain active, rather than directly activating YES to activate YAP ( 93 ).…”