The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

Abstract

The vast majority of colorectal cancer-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 () and aldehyde dehydrogenase A1 () were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis. http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg .

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…The miR-371-373 cluster can act either as tumor-suppressors (Langroudi et al, 2015;Ullmann et al, 2018) or potential oncogenes (Wei et al, 2015;Ghasemi et al, 2018) in various human malignancies. In HBV infection, the upregulation of miRs-372-373 has been shown to positively correlate with the number of HBV DNA copies.…”

LncRNA MIR4435‐2HG potentiates the proliferation and invasion of glioblastoma cells via modulating miR‐1224‐5p/TGFBR2 axis

“…In addition, TGFBR2 has also been identified as a novel regulator of GBM stemness, 29 which may be related to the platelet‐derived growth factor receptor inhibitor resistance in GBM treatment 30 . TGFBR2 exerted the tumour‐enhancing effects via targeting different downstream mediators such as inhibitor of DNA binding, 31 Smad2/3 32 and p53 33 in other types of cancers. Moreover, several miRNAs including miR‐181c, 34 miR‐373 35 and miR‐502c 36 suppressed GBM progression via the inhibition of TGFBR2 expression.…”

<p>MicroRNA-371-3 cluster as biomarkers for the diagnosis and prognosis of cancers</p>

“…In metastasisderived tumor initiated cells (TICs), TGFβ receptor 2 (TGFBR2), an identified target of miR-371-3, were repressed and the miR-371-3/TGFBR2/inhibitor of DNA binding 1 signaling pathway showed credible connection to self-renewal of TIC. 7 MiR-373 regulated tumor cell proliferation and growth by prohibiting or enhancing multiple target genes expression, including large tumor suppressor homolog 2 (LATS2), 12,36 CD44, 14 nuclear factor I/B (NFIB), 37 and estrogen receptor (ER). 38 Moreover, the stemness of CRC cells was enhanced by miR-372/373 via repressing differentiationrelated pathways, such as NFκB, MAPK/Erk, and VDR.…”

“…MicroRNA-371-3 (miR-371-3) cluster locates on chromosome 19 and has three members, miR-371, MiR-372 and miR-373. MiR-371-3 cluster has been discussed to be involved in several diseases, such as canine visceral leishmaniasis, 4 stroke, 5 Kawasaki diseases, 6 colon cancer, 7 and moreover, it's role in the pathology of cancers is currently being focused on in several studies. [8][9][10][11] MiR-372 and miR-373 were reported to have the capacity to activate wild-type p53, counteract p53-mediated CDK inhibition and nourish oncogenic RAS to promote testicular germ cell cancerous process, 12 and up regulated miR-371-3p could reverse the acquired drug resistance and improve overall survival of cancer patients.…”