DDX17 induces epithelial-mesenchymal transition and metastasis through the miR-149-3p/CYBRD1 pathway in colorectal cancer

Abstract

DEAD box helicase 17 (DDX17) has been reported to be involved in the initiation and development of several cancers. However, the functional role and mechanisms of DDX17 in colorectal cancer (CRC) malignant progression and metastasis remain unclear. Here, we reported that DDX17 expression was increased in CRC tissues compared with noncancerous mucosa tissues and further upregulated in CRC liver metastasis compared with patient-paired primary tumors. High levels of DDX17 were significantly correlated with aggressive phenotypes and worse clinical outcomes in CRC patients. Ectopic expression of DDX17 promoted cell migration and invasion in vitro and in vivo, while the opposite results were obtained in DDX17-deficient CRC cells. We identified miR-149-3p as a potential downstream miRNA of DDX17 through RNA sequencing analysis, and miR-149-3p displayed a suppressive effect on the metastatic potential of CRC cells. We demonstrated that CYBRD1 (a ferric reductase that contributes to dietary iron absorption) was a direct target of miR-149-3p and that miR-149-3p was required for DDX17-mediated regulation of CYBRD1 expression. Moreover, DDX17 contributed to the metastasis and epithelial to mesenchymal transition (EMT) of CRC cells via downregulation of miR-149-3p, which resulted in increased CYBRD1 expression. In conclusion, our findings not only highlight the significance of DDX17 in the aggressive development and prognosis of CRC patients, but also reveal a novel mechanism underlying DDX17-mediated CRC cell metastasis and EMT progression through manipulation of the miR-149-3p/CYBRD1 pathway.

Update on the association of miR-149 rs2292832 C>T polymorphism with gastric cancer risk: A meta-analysis study of gastrointestinal cancers

“…[9,13] The miR-149 targets different genes and pathways and plays a dual role in proliferation and apoptosis, in some cancers such as leukemia, glioblastoma, prostate, and melanoma, mir-149 is upregulated and acts as an onco-miRNA, but in the lung, and gastric, hepatocellular, colorectal, and breast cancers are downregulated and known as tumor suppressor, [18] some factors such as FOXC1, ADAM12, CYBRD1, and ZBTB2 have been identified as targets of miR-149 to exert its function on cell proliferation and cancer metastases. [7,8,[19][20][21] Cytological experiments have confirmed that miRNA-149 inhibits the biological behavior of GC by targeting FOXC1, [8] but its role in clinical needs to be defined.…”

The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

“…137 DEAD-box helicase 17 (DDX17) is a multifunctional ATP-dependent RNA/DNA helicase that is involved in the initiation and development of a variety of tumours. 138 In NSCLC, the upregulation of DDX17 is associated with increased gefitinib resistance, while the silencing of DDX17 can partially reverse this sensitivity. 139 One study showed that increased DDX17 expression promoted β-catenin transcriptional activity.…”

“…Despite the initial efficacy of EGFR‐TKIs, approximately 65% of EGFR‐TKI‐sensitive NSCLC patients develop resistance to these medications within 9 to 13 months of treatment 137 . DEAD‐box helicase 17 (DDX17) is a multifunctional ATP‐dependent RNA/DNA helicase that is involved in the initiation and development of a variety of tumours 138 . In NSCLC, the upregulation of DDX17 is associated with increased gefitinib resistance, while the silencing of DDX17 can partially reverse this sensitivity 139 .…”

RNA-binding proteins and exoribonucleases modulating miRNA in cancer: the enemy within

“…Moreover, DDX17 was reported to augment cancer-associated features by inhibiting miRNAs. DDX17 can promote EMT and metastasis in colorectal cancer (CRC) by mediating the miR-149-3p/CYBRD1 axis 181 . The expression of the tumor-suppressive miR-149-3p is reduced by DDX17, resulting in increased expression of its target CYBRD1.…”