Stearoyl-CoA-desaturase-1 regulates gastric cancer stem-like properties and promotes tumour metastasis via Hippo/YAP pathway

Abstract

Background Stearoyl-CoA desaturase-1 (SCD1) is reported to play essential roles in cancer stemness among several cancers. Our previous research revealed significant overexpression of SCD1 in primary gastric cancer stem cells (GCSCs), with its functional role still unknown. Methods We stably established three primary GCSCs by sphere-forming assays and flow cytometry. Protein quantification and bioinformatics analysis were performed to reveal the differential protein pattern. Lentivirus-based small-interfering RNA (siRNA) knockdown and pharmacological inhibition approaches were used to characterise the function and molecular mechanism role of SCD1 in the regulation of GC stemness and tumour metastasis capacity both in vitro and in vivo. Results SCD1 was found to increase the population of GCSCs, whereas its suppression by an SCD1 inhibitor or knockdown by siRNA attenuated the stemness of GCSCs, including chemotherapy resistance and sphere-forming ability. Furthermore, SCD1 suppression reversed epithelial-to-mesenchymal transition and reduced the GC metastasis probability both in vitro and in vivo. Downregulation of SCD1 in GCSCs was associated with the expression of Yes-associated protein (YAP), a key protein in the Hippo pathway, and nuclear YAP translocation was also blocked by the SCD1 decrease. Conclusions SCD1 promotes GCSC stemness through the Hippo/YAP pathway. Targeting SCD1 might be a novel therapeutic strategy, especially to suppress GC metastasis and sensitise chemotherapy.

MiR-144-3p inhibits gastric cancer progression and stemness via directly targeting GLI2 involved in hedgehog pathway

“…Adherent cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, GIBCO, NY, USA) with 10% fetal bovine serum (FBS) and 1% P/S in a standard condition at 37 °C with 5% CO 2 . Gastric cancer stem cells (GCSCs) were obtained and cultured as previously described [ 13 , 14 ]. Briefly, GCSCs were extracted from fresh GC tissues resected in Chinese PLA General Hospital (PLAGH) and cultured in ultra-low-attachment 6-well plates (Corning, NY, USA) with modified DMEM/F12, 2% B27 supplements (Invitrogen, CA, USA), 1% ITS (insulin–transferrin–selenous acid, Corning, NY, USA), 20 ng/ml epidermal growth factor (Peprotech, Hartford, CT, USA), 10 ng/ml basic fibroblast growth factor (Peprotech), 10 ng/ml LIF (Peprotech) and 10 ng/ml gastrin I (Peprotech).…”

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy

“…It has been observed that the expression of SCD1 is upregulated in hepatocellular, renal clear cell, lung, prostate and breast cancer, which is associated with poorer prognosis (Fritz et al, 2010;Holder et al, 2013;von Roemeling et al, 2013;Huang et al, 2015;Wohlhieter et al, 2020). Recent evidence also supported that SCD1 involved in many tumor-related pathways and played important roles in the self-renewal, metastasis, and resistance to therapy in glioblastoma, breast, lung and bladder CSCs (Noto et al, 2013;Colacino et al, 2016;Li J. et al, 2017;Mukherjee et al, 2017;Noto et al, 2017;Pisanu et al, 2018;Pinkham et al, 2019;Gao et al, 2020;Yu et al, 2021).…”

“…The inhibition of SCD1 led to the selective elimination of colon CSCs through suppressing Wnt and Notch signaling ( Yu et al, 2021 ). The results showed that the crosstalk between SCD1 and Hippo pathway played an important role in maintaining the stemness features of the lung, gastric, and melanoma CSCs ( Noto et al, 2017 ; Pisanu et al, 2018 ; Gao et al, 2020 ). Besides, the Notch signaling pathway mediated the homeostasis of liver cancer cells by controlling FAO by mediating the expression of the FAO-associated genes ( Song et al, 2016 ).…”

Gastric Cancer Stem Cells: A Glimpse on Metabolic Reprogramming

“…In gastric cancer, SCD1 has found to be upregulated and this results in poor survival rates. Furthermore, this enzyme is able to induce tumorigenesis, drug resistance and metastasis by regulating GCSCs proliferation through the Hippo pathway ( 79 ). Hence CSCs, compared to their differentiated tumor counterparts, show an enhancement of lipid synthesis de novo , which is also reflected in the accumulation of intracellular lipids.…”