Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells

Abstract

BackgroundObesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown.MethodsWe hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion.ResultsOf ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2.ConclusionsOur findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2938-1) contains supplementary material, which is available to authorized users.

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

“…The thyroid hormone receptor activator THRA gene is integrated and linked to obesity [84][85][86]. The NCOA1 gene in adipocytes has also been shown to be associated with metabolic disease [87][88][89]. The KSR2 gene [60,90,91] and FGF21 [92][93][94] are also integrated genes in the network associated with obesity, Figure 7 and S3.…”

Microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promotes liver metastasis of breast cancer

“…Another study showed that miR‐4443 promoted Epi resistance in non‐small‐cell lung cancer by downregulating inositol polyphosphate‐4‐phosphatase Type I A and activating Janus kinase 2/signal transducer and activator of transcription 3 pathway (W. Zhang et al, 2018). However, miR‐4443 showed a beneficial effect in ovarian cancer, glioblastoma, osteosarcoma, hepatocellular carcinoma, and colon cancer (Ebrahimi & Reiisi, 2019; Gao et al, 2019; Gong, Wang, Liu, Hu, & Zheng, 2018; Meerson & Yehuda, 2016; C. Zhou et al, 2018). Taking together, miR‐4443 may play different roles in different cancers.…”

The oncogenic roles of nuclear receptor coactivator 1 in human esophageal carcinoma

“…Signaling pathways involved in the sex steroid receptors play important roles not only in cancers typically responsive to sex hormones (ie, breast and prostate cancers) but also those classically considered as nonhormone responsive such as lung, liver, kidney, skin, and gastrointestinal cancers. [1][2][3] Functionally, sex steroid receptors such as estrogen receptor (ER) and androgen receptor (AR) serve as transcription factors by recruiting multiple coactivators. 4,5 By collaborating with transcription factors, coactivators play crucial roles in chromatin remodeling and regulation of gene expression.…”