Brg-1 targeting of novel miR550a-5p/RNF43/Wnt signaling axis regulates colorectal cancer metastasis

Abstract

Metastasis is one of the main causes of death in patients with colorectal cancer (CRC). Brg-1 is a central component of the SWItch/Sucrose NonFermentable chromatin-remodeling complex, which features a bromodomain and helicase/ATPase activity. The gene encoding Brg-1 is frequently mutated or silenced in human cancers. Several reports have proposed Brg-1 as a tumor suppressor; however, little is known about its role in oncogenesis and metastasis. Here we demonstrated that decreased Brg-1 regulates a novel miR-550a-5p/RNF43/Wnt/β-catenin signaling pathway, to promote CRC metastasis in vitro and in vivo. In particular, we used high-throughput RNA-sequencing analysis to show that Brg-1 negatively regulates miR-550a-5p in CRC cells. We further found that Brg-1 inhibits the transcriptional activity of miR-550a-5p promoter, and that decreased Brg-1 expression increased miR-550a-5p expression. We also identified ring finger 43 (RNF43), an inhibitor of Wnt/β-catenin signaling, as a target of miR-550a-5p. Knockdown of Brg-1 by small interfering RNA led to decreased RNF43 expression, increased Wnt signaling and increased CRC cell migration and invasion. This novel pathway defines a new function for Brg-1 and provides potential targets for the treatment of Brg-1 mutant and loss-of-function tumors.

BRG1 targeting STAT3/VEGFC signaling regulates lymphangiogenesis in colorectal cancer

“…In our previous study, we reported that BRG1 expression is related with lymph node metastases [13]. To further confirm this finding, we measured the expression levels of BRG1 in lymph node metastases and primary tumors from 180 patients with lymph node metastatic CRC by immunohistonchemistry, after which we rated the amount of BRG1 staining by using an immunoreactive score (IRS) (Figure 1A and 1B).…”

“…In addition, BRG1 has been shown to interact with the tumor suppressor, p53, thereby leading to the transcriptional activation of target genes, including tumor suppressors such as prohibitin, TopBP1 and HIC1 [20–22]. In our previous study, we have shown that mutant or loss functional BRG1 promoted colon cancer metastasis in vitro and in vivo [13]. In this study, we investigated the function of BRG1 in cancer-related lymphangiogenesis.…”

“…Mutations of BRG1 and silencing of BRG1 protein expression have been observed in several cancers; moreover, BRG1−/+ in heterozygous mice has led to increased tumor development, suggesting that BRG1 may act as a tumor suppressor [11, 12]. Previously, we have reported that decreased BRG1 expression plays a critical role in CRC metastasis; we also reported that the BRG1 loss function could promote colon cancer cell migration and invasion and that the BRG1 expression level is negatively correlated with lymphatic metastasis [13]. Given that lymphangiogenesis is an important early event and a promoting factor that induces lymphatic metastasis, we hypothesize that BRG1 may also play an important role in lymphangiogenesis.…”

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…Our quest revealed that ring finger 43 (RNF43) is an experimentally verified target of miR-550a-5p in colorectal cancer cells. (96) Interestingly, RNF43 was found to negatively regulate Wnt/bcatenin, (97) which in turn is known to inhibit osteoclastogenesis. (98) Further studies are necessary to elucidate whether this miR-550a-5p/RNF43/WNT pathway is also active in bone.…”

MicroRNA-375 suppresses human colorectal cancer metastasis by targeting Frizzled 8

“…Among these pathways, Wnt/β-catenin signaling is known to play a major role in the promotion of CRC metastasis [43] and correlates with poor clinical prognosis [44]. Hu et al found that several factors, such as stromal cell-derived factors, can induce the Wnt/β-catenin pathway to promote CRC progression [45], whereas Wang et al showed that Brg-1 can inhibit the Wnt/β-catenin pathway to suppress CRC metastasis [46]. Moreover, nuclear β-catenin accumulation, another important feature of Wnt/β-catenin signaling activation, has frequently been observed in primary CRC tissues [40], which further highlights the essential role of Wnt/β-catenin in the process of metastasis.…”