Upregulation of miR-199a/b contributes to cisplatin resistance via Wnt/ß-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells.

Cisplatin resistance in colorectal cancer largely results from the colorectal cancer stem cells which could be targeted to improve the efficacy of chemotherapy. MicroRNAs are possible modulators of cancer stem cell characteristics and maybe involved in the retention of cancer stem cell chemoresistance. The aim of this study was to investigate the biological function of miR-199a/b on cisplatin resistance in colorectal cancer stem cells and its related mechanisms. Here, ALDHA1+ cells from primary colorectal cancer tissues behaved similar to cancer stem cells and were chemoresistant to cisplatin. The presence of a variable fraction of ALDHA1 was detected in 9 out of 10 colorectal cancer specimens. Significantly, increased miR-199a/b expression was detected in ALDHA1+ colorectal cancer stem cells, accompanied by a downregulation of Gsk3ß and an overexpression of ß-catenin and ABCG2. In patient cohort, enhanced miR-199a/b expression in colorectal cancer tissues was associated with cisplatin response and poor patient survival. In addition, 80% of colorectal cancer samples showed lower level of Gsk3ß than their adjacent normal counterparts. Furthermore, Gsk3ß was the direct target of miR-199a/b. MiR-199a/b regulated Wnt/ß-catenin pathway by targeting Gsk3ß in ALDHA1+ colorectal cancer stem cells. By blocking Wnt/ß-catenin pathway, we implied that ABCG2 lies downstream of Wnt/ß-catenin pathway. ABCG2 was further demonstrated to contribute cisplatin resistance in ALDHA1+ colorectal cancer stem cells and can be regulated by miR-199a/b. Thus, our data suggested that upregulation of miR-199a/b in ALDHA1+ colorectal cancer stem cells contributed to cisplatin resistance via Wnt/ß-catenin-ABCG2 signaling, which sheds new light on understanding the mechanism of cisplatin resistance in colorectal cancer stem cells and facilitates the development of potential therapeutics against colorectal cancer.

Basic Transcription Factor 3 Is Required for Proliferation and Epithelial-Mesenchymal Transition via Regulation of FOXM1 and JAK2/STAT3 Signaling in Gastric Cancer.

Gastric cancer (GC) is the most common epithelial malignancy worldwide. Basic transcription factor 3 (BTF3) plays a crucial role in the regulation of various biological processes. We designed experiments to investigate the molecular mechanism underlying the role of BTF3 in GC cell proliferation and metastasis. We confirmed that BTF3 expression was decreased in GC tissues and several GC cell lines. Lentivirus-mediated downregulation of BTF3 reduced cell proliferation, induced S and G2/M cell cycle arrest, and increased apoptosis. Knockdown of BTF3 significantly reduced the expression of Forkhead box M1 (FOXM1). Upregulation of FOXM1 significantly inhibited the decrease in cell proliferation due to BTF3 silencing, S and G2/M cell cycle arrest, and increase in apoptosis. Knockdown of BTF3 decreased Ki-67 and PCNA expression, whereas it increased p27 expression, which was inhibited by upregulation of FOXM1. Knockdown of BTF3 significantly decreased the ability to invade and migrate. Moreover, knockdown of BTF3 increased E-cadherin expression, whereas it decreased N-cadherin and ZEB2 expression, indicating a decrease in epithelial-mesenchymal transition (EMT). Phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) was significantly inhibited by knockdown of BTF3. IL-6-stimulated phosphorylation of STAT3 and JAK2 markedly suppressed inhibition of EMT due to BTF3 silencing. Silencing of BTF3 decreased tumor volume and weight and reduced peritoneal nodules in implanted tumors. Our findings provide a novel understanding of the mechanism of GC and highlight the important role of BTF3/FOXM1 in tumor growth and BTF3/JAK2/STAT3 in EMT and metastasis.