TY - JOUR
T1 - APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b
AU - Antoniali, Giulia
AU - Dalla, Emiliano
AU - Mangiapane, Giovanna
AU - Zhao, Xiaolong
AU - Jing, Xinming
AU - Cheng, Yi
AU - De Sanctis, Veronica
AU - Ayyildiz, Dilara
AU - Piazza, Silvano
AU - Li, Mengxia
AU - Tell, Gianluca
N1 - © 2022. The Author(s).
PY - 2022/7/25
Y1 - 2022/7/25
N2 - Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. We validated DICER1 as a direct functional target of the APE1-regulated miRNA-33a-5p and miR-130b-3p. Importantly, IHC analyses of different human tumors confirmed a negative correlation existing between APE1 and Dicer1 protein levels. DICER1 downregulation represents a prognostic marker of cancer development but the mechanisms at the basis of this phenomenon are still completely unknown. Our findings, suggesting that APE1 modulates DICER1 expression via miR-33a and miR-130b, reveal new mechanistic insights on DICER1 regulation, which are of relevance in lung cancer chemoresistance and cancer invasiveness.
AB - Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. We validated DICER1 as a direct functional target of the APE1-regulated miRNA-33a-5p and miR-130b-3p. Importantly, IHC analyses of different human tumors confirmed a negative correlation existing between APE1 and Dicer1 protein levels. DICER1 downregulation represents a prognostic marker of cancer development but the mechanisms at the basis of this phenomenon are still completely unknown. Our findings, suggesting that APE1 modulates DICER1 expression via miR-33a and miR-130b, reveal new mechanistic insights on DICER1 regulation, which are of relevance in lung cancer chemoresistance and cancer invasiveness.
KW - Cancer
KW - Gene signatures
KW - miRnome
KW - Network analysis
KW - Ribonuclease III/genetics
KW - Lung Neoplasms/pathology
KW - Down-Regulation
KW - Humans
KW - Gene Expression Regulation, Neoplastic
KW - DEAD-box RNA Helicases/genetics
KW - Carcinoma, Non-Small-Cell Lung/genetics
KW - Cell Line, Tumor
KW - MicroRNAs/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85134758301&partnerID=8YFLogxK
U2 - 10.1007/s00018-022-04443-7
DO - 10.1007/s00018-022-04443-7
M3 - Article
C2 - 35876890
AN - SCOPUS:85134758301
SN - 1420-682X
VL - 79
SP - 446
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 8
M1 - 446
ER -