Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer
Open Access
- 21 July 2020
- Vol. 12 (8), 2011
- https://doi.org/10.3390/cancers12082011
Abstract
Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory factor receptor (LIFR) and its ligand LIF in breast cancer. This study aimed to determine LIF’s effect on CSC properties in GC cell lines and patient-derived xenograft (PDX) cells, which remains unexplored. LIF’s treatment effect on CSC markers expression and tumoursphere formation was evaluated. The Hippo kinase inhibitor XMU-MP-1 and/or the JAK1 inhibitor Ruxolitinib were used to determine Hippo and canonical JAK/STAT pathway involvement in gastric CSCs’ response to LIF. Results indicate that LIF decreased tumorigenic and chemo-resistant CSCs, in both GC cell lines and PDX cells. In addition, LIF increased activation of LATS1/2 Hippo kinases, thereby decreasing downstream YAP/TAZ nuclear accumulation and TEAD transcriptional activity. LIF’s anti-CSC effect was reversed by XMU-MP-1 but not by Ruxolitinib treatment, highlighting the opposite effects of these two pathways downstream LIFR. In conclusion, LIF displays anti-CSC properties in GC, through Hippo kinases activation, and could in fine constitute a new CSCs-targeting strategy to help decrease relapse cases and bad prognosis in GC.Keywords
Funding Information
- Institut National Du Cancer (PLBio 2014-152)
This publication has 47 references indexed in Scilit:
- Association of RASSF1A promoter methylation with gastric cancer risk: a meta-analysisTumor Biology, 2013
- Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern ChinaBMC Cancer, 2013
- LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic markerNature Medicine, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- LIF-Dependent Signaling: New Pieces in the LegoStem Cell Reviews and Reports, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Leukemia Inhibitory Factor Downregulates Human Papillomavirus-16 Oncogene Expression and Inhibits the Proliferation of Cervical Carcinoma CellsInfectious Diseases in Obstetrics and Gynecology, 2011
- A Randomized, Double-Blinded, Placebo-Controlled Phase II Trial of Recombinant Human Leukemia Inhibitory Factor (rhuLIF, Emfilermin, AM424) to Prevent Chemotherapy-Induced Peripheral NeuropathyClinical Cancer Research, 2005
- Differentiation inhibiting activity () and mouse developmentDevelopmental Biology, 1992
- Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cellsNature, 1988