lncRNA GAS5 Reverses EMT and Tumor Stem Cell-Mediated Gemcitabine Resistance and Metastasis by Targeting miR-221/SOCS3 in Pancreatic Cancer

Abstract

Dysregulated long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) mediating chemotherapeutic drug effects and metastasis in pancreatic cancer (PC) are key reasons for the poor prognosis of this disease. lncRNA growth arrest-specific 5 (GAS5) is reported to be a tumor suppressor in multiple cancers. However, the functions of GAS5 and its related miRNAs in PC are poorly understood. This study explored the potential functions and mechanisms of GAS5 in PC gemcitabine resistance and metastasis. The results show that overexpression of GAS5 suppressed the proliferation, migration, gemcitabine resistance, stem cell-like properties, and epithelial-mesenchymal transition (EMT) of PC cells by directly binding to and suppressing miR-221 expression and enhancing suppressor of cytokine signaling 3 (SOCS3) expression. The effects of miR-221 overexpression on proliferation, migration, gemcitabine resistance, stem cell-like properties, and EMT inhibition were reversed by SOCS3 overexpression in PC cells. Additionally, GAS5 promoted gemcitabine-induced tumor growth and metastasis inhibition, as determined by Ki-67 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), bioluminescence imaging, and the detection of cell-like properties and EMT in vivo. Thus, lncRNA GAS5 functioned as a competing endogenous RNA for miR-221, and it suppressed cell growth, metastasis, and gemcitabine resistance in PC by regulating the miR-221/SOCS3 pathway mediating EMT and tumor stem cell self-renewal.

The interplay between m6A RNA methylation and noncoding RNA in cancer

“…the proliferation, invasion, migration, epithelial mesenchymal transition (EMT), and radiation resistance of cancer cells [101][102][103]. LncRNA GAS5-AS1 is the antisense RNA of GAS5, and its downregulation is closely related to the TNM stage, lymph node metastasis, and prognosis of tumors, such as NSCLC and liver cancer [104,105].…”

Non-coding RNAs in Pancreatic Ductal Adenocarcinoma

“…Studies have shown that GAS5 inhibits drug resistance in PDAC by negative regulation of miR-181c-5p and reducing the inactivation of the Hippo signal transduction pathway (61). Overexpression of GAS5 inhibits PDAC cell proliferation, migration and gemcitabine resistance through miR-221/suppressor of cytokine signaling 3 (SOCS3) mediated EMT and tumor CSCs (62).…”

Upregulation of hsa_circ_0007874 suppresses the progression of ovarian cancer by regulating the miR‐760/SOCS3 pathway

“…Previous studies validated that SOCS3 expression is downregulated in cancer tissues, including pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, and breast cancer . SOCS3 overexpression has an anti‐proliferative and anti‐metastatic effect in cancer . Previous studies have found that when a cytokine or a growth factor binds to an intracellular receptor as a ligand, the receptor can form a heterodimer and phosphorylate the JAK kinase.…”

“…[32][33][34][35][36] SOCS3 overexpression has an anti-proliferative and anti-metastatic effect in cancer. 37,38 Previous studies have found that when a cytokine or a growth factor binds to an intracellular receptor as a ligand, the receptor can form a heterodimer and phosphorylate the JAK kinase. Activated JAK can phosphorylate the tyrosine residue of STAT and activated STAT is separated from the receptor complex, forms a dimer, and is translocated from the cytoplasm to the nucleus, where it acts on specific DNA fragments and regulates gene transcription and expression.…”