MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

Abstract

BACKGROUND: Chemoresistance remains a critical event that accounts for colorectal cancer (CRC) lethality. The aim of this study is to explore the ability of dichloroacetate (DCA) to increase chemosensitivity in CRC and the molecular mechanisms involved. METHODS: The effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. The DCAresponsive proteins in AMPK pathway were enriched using proteomic profiling technology. The effect of DCA on CAB39-AMPK signal pathway was analysed. In addition, miRNA expression profiles after DCA treatment were determined. The DCA-responsive miRNAs that target CAB39 were assayed. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39-AMPK-mTOR signalling pathway. RESULTS: DCA increased L-OHP chemosensitivity both in vivo and in vitro. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. CAB39 was confirmed to be a direct target of miR-107 regulated by DCA. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo. CONCLUSION: These findings suggest that the miR-107 induces chemoresistance through CAB39-AMPK-mTOR pathway in CRC cells, thus providing a promising target for overcoming chemoresistance in CRC.

CAB39 mediates epithelial-mesenchymal transition via activation of NF-κB signaling to facilitate bladder cancer invasion and metastasis

“…Consistently, Kelley and colleagues measured the expression of CAB39 in rectal cancer patients with or without response to radiotherapy and found a signi cantly higher CAB39 level in patients without response than those with complete or partial response [39]. However, Liang et al have found that CAB39 was upregulated as a result of treatment of dichloroacetate (DHA) and associated with increased chemosensitivity to oxaliplatin [30]. In addition, a recent report has suggested that CAB39 act as a tumor suppressor in pancreatic cancer, which inhibits cell proliferation, reduces cell invasion, promotes cell apoptosis, and induces cell cycle arrest in pancreatic cancer cell lines PANC-1 and AsPC-1 [40].…”

“…From analysis of TCGA database, Ruhl et al noted increased CAB39 expression at the protein level in a signi cant portion of colon cancer patients associated with poorer overall survival [23]. Additionally, studies on microRNAs targeting CAB39 in gastric cancer, lung cancer, colorectal cancer, and glioma also suggest that CAB39 upregulation has stimulatory effect on cell proliferation, invasion, and oncogenic autophagy [25,[29][30][31]. Since CAB39 is evolutionarily conserved and ubiquitously expressed in a variety of human tissues, its oncogenic function is likely to be fundamental in most cell types and the association with tumor invasion and metastasis observed in BC can also occur in other types of cancers [32].…”

“…Since previous studies have revealed enhanced CAB39 expression in many types of cancers including colorectal cancer, gastric cancer, and hepatocellular cancer promoting cell proliferation and metastasis, the oncogene has become a favorable target for the treatment of these types of cancers. [23,25,[29][30][31][32]. Ruhl et al Found that in response to g-radiation, a speci c miRNA-451a could be rapidly upregulated to target and degrade CAB39 [23].…”

Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells

“…Previous studies have indicated that miR-107 is a tumor suppressor in many cancers such as lung cancer [ 40 ], melanoma [ 41 ], and oral squamous cell carcinoma [ 42 ]. However, other studies have shown that miR-107 can induce chemoresistance in colon cancer by targeting calcium-related proteins [ 43 ]. Further, miR-107 reportedly promotes HCC cell proliferation by targeting axin2 [ 44 ].…”

Circulating Exosomal MiR-107 Restrains Tumorigenesis in Diffuse Large B-Cell Lymphoma by Targeting 14-3-3η

“…Breast cancer ↓ Inhibits cell proliferation, cell-cycle and invasion through BDNF (Ai et al, 2018) ↓ Inhibits cell proliferation, colony formation, migration and invasion and promotes apoptosis through targeting SIAH1 (Zhang et al, 2016) ↓ Relates with histological grade index of ER-positive breast cancer (Tsunoda et al, 2018) ↑ Performs predictive role in the triple-negative breast cancer (Hong et al, 2020;Terkelsen et al, 2020) Gastric cancer ↑ Associates with tumor progression characteristics and acts as an independent prognostic factor for OS and DFS (Inoue et al, 2012) ↑ Promotes cell growth, migration, and invasion by targeting NF1 (Wang S. et al, 2016) Lung cancer ↓ Inhibits cell proliferation, migration and arrest cell cycle by targeting TGFβR2 ↓ Inhibits paclitaxel resistance, metastasis, proliferation and survival through Bcl-w/PI3K-AKT (Lu et al, 2017) ↓ Inhibits cancer progression by targeting EGFR (Wang et al, 2017) ↓ Correlates with tumor progression characteristics and inhibits cancer growth by targeting BDNF and PI3K/AKT pathway (Xia et al, 2016) Hepatocellular carcinoma ↑ Promotes tumor progression through miR-107/CPEB3/EGFR axis (Zou et al, 2016) Renal cell carcinoma ↓ Inhibits cell proliferation and invasion by targeting EIF5 (Song et al, 2015) Meningioma ↓ Correlates with the increasing histopathological grade (Katar et al, 2017) Prostate cancer MiR-107-miR-26b-5p predict prostate cancer with AUC = 0.93 and p = 0.0012 (Lekchnov et al, 2018) Glioblastomas ↓ MiR-107-miR-331 associate with poorer prognosis (p = 0.033) (Hermansen et al, 2017) Colorectal cancer ↑ Induces chemoresistance through CAB39-AMPK-mTOR pathway (Liang et al, 2020) HOTAIRM1/miR-107/TDG axis regulates cell proliferation, invasion, and migration (Li et al, 2020) ↑, Upregulation; ↓, Downregulation.…”