Deregulation of CSMD1 targeted by microRNA-10b drives gastric cancer progression through the NF-κB pathway

Abstract

Aim:This study aimed to investigate the oncogenic activity of microRNA-10b by targeting CUB and sushi multiple domains protein 1 (CSMD1) in human gastric cancer (GC) and the underlying mechanisms. Methods: The expression of CSMD1 in human GC tissues was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical analysis. The expressive abundance of microRNA-10b was detected by stem-loop RT-PCR. Molecular and cellular techniques, including lentiviral vector-mediated knockdown or overexpression, were used to elucidate the effect of microRNA-10b on the expression of CSMD1. Results: CSMD1 was targeted and downregulated by microRNA-10b in human GC tissues and cells, and the down-regulated expression of CSMD1 contributed to poor survival. The knockdown of microRNA-10b expression inhibited cell proliferation in GC cells in vitro and tumor growth in vivo. The inhibition of microRNA-10b expression repressed invasion and migration of HGC27 cells and retarded GC cells metastasis to the liver in Balb/c nude mice. The up-regulated expression of microRNA-10b promoted the proliferation and metastasis of MKN74 cell in vitro. Intratumoral injection of microRNA-10b mimic also promoted the growth and metastasis of tumor xenografts in Balb/c nude mice. Mechanistically, microRNA-10b promoted the invasion and metastasis of human GC cells through inhibiting the expression of CSMD1, leading to the activation of the nuclear factor-κB (NF-κB) pathway that links inflammation to carcinogenesis, subsequently resulting in the upregulation of c-Myc, cyclin D1 (CCND1), and epithelial-mesenchymal transition (EMT) markers. Conclusions: The findings established that microRNA-10b is an oncomiR that drives metastasis. Moreover, a set of critical tumor suppressor mechanisms was defined that microRNA-10b overcame to drive human GC progression.

The Role of Csmd1 during Mammary Gland Development

“…CSMD1 has been characterised, using a range of in vivo and in vitro approaches, and is implicated in various processes, such as testicular development, complement regulation, schizophrenia and in cancer progression [ 9 , 10 , 11 , 12 , 13 ]. In relation to cancer, CSMD1 has been identified as a tumour suppressor with previous studies identifying the chromosome location 8p23 as an area deleted in various cancers, such as breast, head and neck and colorectal [ 1 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Furthermore CSMD1 deletion has also been linked to poor prognosis in patients with late stage breast cancer [ 12 , 17 , 20 , 21 ].…”

“…These studies show that pregnant mice have increased ductal growth when Csmd1 is knocked out and in-vitro ductal studies identify more rapid cell growth and duct formation in CSMD1 KO cells [ 11 , 22 ]. These studies, along with further characterisation studies of CSMD1, have identified that the deletion of CSMD1 causes increased cell invasion, motility and proliferation [ 14 , 15 , 22 , 23 ]. These studies therefore suggest a potential role for CSMD1 in the regulation of epithelial mesenchymal transition (EMT).…”

“…EMT is the process by which functional epithelial cells are able to revert back to a stem cell state, which allows the cells to become more proliferative and migratory [ 24 , 25 , 26 ]. Furthering the connection between Csmd1 and EMT showed a connection between Csmd1 and Nf-κß, a well-known EMT factor, where Csmd1 inhibition leads to increased Nf-κß activity and increased EMT phenotype in gastric cancer [ 14 , 27 ]. Along with changes in Nf-κß signalling, alterations in Smad signalling have also been identified to be associated with changes in Csmd1 expression [ 13 , 15 , 28 ].…”

“…In this study specific protein expression patterns were analysed to determine changes Csmd1 KO has on their expression. Proteins were selected primarily due to their connection to EMT regulation, a mechanism which Csmd1 has previously been suggested to be involved in regulating [ 14 , 15 , 22 , 23 ]. A range of proteins were analysed in order to narrow down the specific EMT pathway Csmd1 regulates.…”

MicroRNA 452 Regulates Cell Proliferation, Cell Migration, and Angiogenesis in Colorectal Cancer by Suppressing VEGFA Expression

“…They also affect the pathogenesis of various cancer types by functioning as oncogenes or tumor suppressor genes [8,9,10,11]. More recently, accumulating reports suggest that miRNAs are associated the various forms of tumorigenesis including lung cancer [12,13,14], prostate cancer [15,16], gastric cancer [17,18], and liver cancer [19,20]. Therefore, characterization of the correlations between miRNAs and their target genes in cancer cells may have a substantial diagnostic, prognostic, and therapeutic value.…”