miR‐372 and miR‐373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways

Abstract

miR‐372/373, a cluster of stem cell‐specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR‐372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR‐372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24‐positive cell population and promoting self‐renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA‐induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR‐372/373 and found that stemness‐related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation‐related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR‐372/373. Numerous new targets of miR‐372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR‐372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR‐372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell‐specific microRNAs in the development of metastasis and drug resistance in CRC.

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

“…This study further identifies that ZBTB7A is also under the post-transcriptional control of miR-372 in addition to there being gene copy loss during oral tumorigenesis. Since miR-372 is a prognostic determinant of a wide panel of malignancies (8,11,13), the miR-372-ZBTB7A axis would seem likely to be a therapeutic target when treating such malignancies.…”

“…Since the EMT is highly associated with drug resistance (58), it is likely that the ZBTB7A-TRAIL-R2 axis may also attenuate EMTassociated drug resistance. Since disruptions of the miR-371-miR-373 cluster and the chromosome 19q13 locus are rather common in malignancies (4,6,8,10,(12)(13)(14), genome-wide studies should help with a more comprehensive understanding of how aberrations in the miR-372-ZBTB7A-TRAIL-R2 cascade affect oncogenicity.…”

“…This cluster of miRNAs was originally found to be crucial to the maintenance of stemness in embryonic cells (11). miR-372/miR-373 were then found to be oncogenes that target LATS2, CD44 and various other differentiation regulators active in tumors (12,13). They are upregulated in malignancies and their upregulation of expression of miR-372/miR-373 has been found in HNSCC and miR-372 expression in tumors is a prognostic marker of OSCC (6,8,14).…”

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

“…MiRNA-215 DTL [59] miR-148a WNT, β-catenin [60] miR-199a/b Gsk3β, Wnt/β-catenin-ABCG2 [61] miR-196b-5p STAT3 [62] miRs-31 EphB2 and EphA2 [63] miR-27a Apaf-1/caspase-9 [64] miR-372/373 Nanog, Hedgehog, NFκB, MAPK/Erk, VDR Jak-STAT, TGF-beta, PI3K-Akt, MAPK. [65,66] miR-137 DCLK1 [67] miR-146a β-catenin [68] miR-195-5p STAT3, BIRC5, BCL2, BCL-XL, SOX2, CD133, RBPJ, Notch2 [62,69] Lung miR-128 AKT/ERK, p38, c-met/PI3K/AKT, VEGF/PI3K/AKT, IL-6-JAK-STAT3 [70][71][72][73] miR-181b Notch2 [74] miR-138 TGFβ [75] miR-5100 Rab6 [76] miR-214 c-MYC [76] miR-708-5p Wnt/β-catenin [77] miR-873 miR-125a-3p…”

“…They demonstrated that the upregulated expression of miR-372/373 enhanced CSC features via enrichment of stem-cell-positive cells ultimately responsible for chemoresistance, self-renewal, and metastasis of CRCs. Further, they also elucidated the underlying mechanism of miR-372/373-induced stemness and revealed that activated Nanog and Hedgehog signaling pathways are critically associated with the development and function of stem cells while the functioning of NFκB, mitogen-activated protein kinase (MAPK)/Erk, and VDR signaling mechanisms vital for differentiation was inhibited by miR-372/373, which suggests that miR-372/373 upregulates CRC stemness features via acting on various signaling mechanisms associated with the regulation of stemness and differentiation [65].…”