Journal
CANCER BIOLOGY & THERAPY
Volume 23, Issue 1, Pages 294-309Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2022.2054257
Keywords
Pancreatic cancer; miR-488; ERBB2 (receptor tyrosine-protein kinase2); NE-kappa B; cell cycle signaling
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Funding
- National Natural Science Foundation of China [81873589, 81570585]
- Science and Technology Project of Changsha, Hunan, China [kq2004146]
- Natural Science Foundation of Hunan Province (CN) [2020JJ5876]
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Pancreatic cancer has poor prognosis due to late diagnoses and lack of efficient treatment. MiR-488 expression is downregulated in pancreatic carcinoma, while higher expression is associated with better prognosis. MiR-488 overexpression suppresses malignant behavior of pancreatic tumor cells by inhibiting cell viability, enhancing apoptosis, and inducing cell cycle arrest. MiR-488 targets ERBB2 and NF-kappa B transcriptionally suppresses miR-488 expression, repressing its tumor-suppressive effects.
Pancreatic cancer is one of the malignancies having the poorest prognosis due to late diagnoses and lack of efficient treatment regimens. The identification of potential miRNA-targeted gene axes could act as targets for developing novel treatment strategies. Herein, it was assessed that miR-488 expression was markedly downregulated within pancreatic carcinoma. Higher expression of miR-488 was shown to be linked to better prognosis rates of pancreatic carcinoma as per online data. Within two pancreatic tumor cells, MIA PaCa-2 and PANC-1, miR-488 overexpression significantly suppressed malignant cytological behavior by inhibiting cell viability, enhancing cell apoptosis, and inducing cell cycle G2/M-phase arrest. Moreover, miR-488 overexpression also decreased the protein levels of cell cycle regulators, including cyclin A, cyclin B, CDK1, and CDK2. miR-488 directly targets ERBB2 (receptor tyrosine-protein kinase2) to suppress the expression of ERBB2 by targeting its 3'UTR. ERBB2 knockdown in MIA PaCa-2 and PANC-1 cell lines suppressed, but miR-488 inhibition enhanced the cancer cell biological malignant behavior; the effects of miR-488 inhibition on pancreatic cancer cells were significantly reversed by ERBB2 knockdown. NF-kappa B suppressed the expression of miR-488 transcriptionally via targeting its promoter region, consequentially repressing the tumor-suppressive effects of miR-488 upon pancreatic tumor cells. Thus, an NF-kappa B/miR-488/ERBB2 axis modulating pancreatic cancer cell malignancy and tumor growth through cell cycle signaling was conclusively demonstrated.
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