Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERK pathway

Abstract

miR-3127-5p is a primate-specific miRNA which is down-regulated in recurrent NSCLC tissue vs. matched primary tumor tissue (N = 15) and in tumor tissue vs. normal lung tissue (N = 177). Reduced miR-3127-5p expression is associated with a higher Ki-67 proliferation index and unfavorable prognosis in NSCLC. Overexpression of miR-3127-5p significantly reduced NSCLC cells proliferation, migration, and motility in vitro and in vivo. The oncogene ABL1 was a direct miR-3127-5p target, and miR-3127-5p regulated the activation of the Abl/Ras/ERK pathway and transactivated downstream proliferation/metastasis-associated molecules. Overexpression of miR-3127-5p in A549 or H292 cells resulted in enhanced resistance to dasatinib, an Abl/src tyrosine kinase inhibitor. miR-3127-5p expression levels were correlated with dasatinib sensitivity in NSCLC cell lines without K-Ras G12 mutation. In conclusion, miR-3127-5p acts as a tumor suppressor gene and is a potential biomarker for dasatinib sensitivity in the non-mutated Ras subset of NSCLC.

Downregulation of miR‐3127‐5p promotes epithelial‐mesenchymal transition via FZD4 regulation of Wnt/β‐catenin signaling in non‐small‐cell lung cancer

“…We also verified the consistent relationship between the expressions of miR‐3127‐5p and EMT markers in vivo. However, it should be pointed out that since we observed more lung metastases in miR‐3127‐5p‐inhibited xenografts in our previously reported paper, we just investigated the effects of miR‐3127‐5p on EMT by subcutaneous tumor formation in this study. Moreover, we found that downregulation of miR‐3127‐5p resulted in decreased expression of Vimentin in the lung metastatic tumors, which may be beneficial for tumor colonization.…”

“…Since the in vitro experiments revealed that downregulation of miR‐3127‐5p promotes EMT and cell invasion in NSCLC cell lines, we next asked whether downregulation of miR‐3127‐5p could promote EMT in vivo. In view of the phenomenon that more lung metastases were observed in miR‐3127‐5p‐inhibited xenografts in our previously reported paper, we just investigated the effects of miR‐3127‐5p on EMT by subcutaneous tumor formation in this study. The tumor growth curve indicated that tumors in miR‐3127‐5p inhibition group grew more quickly than tumors in the negative control group (Figure A).…”

“…We previously reported that miR‐3127‐5p was downregulated in NSCLC and its low expression was associated with adverse clinicopathological features. Moreover, we demonstrated that miR‐3127‐5p regulates tumor proliferation, invasion, and metastasis by activating the ABL/Ras/ERK pathway . However, to form metastasis, cancer cells undergo various steps from local invasion to metastatic formation, which are driven by alterations in multiple genes and pathways.…”

“…Many miRNAs are dysregulated in cancer metastasis, and there are likely additional miRNAs involved in this process, which have not yet been identified. We previously demonstrated that miR‐3127‐5p, which functions as a tumor suppressor, is downregulated in NSCLC, and associated with clinical stage and tumor recurrence . However, the precise mechanisms by which miR‐3127‐5p exerts its function in NSCLC metastasis are not well elucidated.…”

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

“…Consistent with these data, downregulation of microRNAs (miRNAs; miRs) that inhibit ABL1/2 expression, also drives disease development. ABL1 is a direct target of miR-3127–5p, which is downregulated in non-small cell lung cancer (NSCLC) patients and is associated with a poor prognosis [44]; miR-3127–5p and ABL1 expression is inversely correlated in patient samples; and loss of miR-3127–5p correlates with dasatinib sensitivity in NSCLC lines lacking KRAS mutations [44]. Likewise, miR-125a-5p, which is downregulated in cervical cancer cell lines and primary tumors, directly targets ABL2, and ABL2 knockdown parallels the effects of miR-212a-5p overexpression on proliferation/migration [45].…”