The endonuclease APE1 processes miR-92b formation, thereby regulating expression of the tumor suppressor LDLR in cervical cancer cells

Abstract

Background: The molecular mechanisms underlying cervical cancer require elucidation to identify novel therapeutic targets. Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is a multifunctional apurinic/apyrimidinic (AP) endonuclease that influences the transcription of many cancer-related genes via microRNome regulation. Herein, we examine the role of miR-92b-3p (hereinafter miR-92b), whose processing may be regulated by APE1, in cervical cancer progression. Methods: APE1’s processing of miR-92b from its pri-miR form was measured by a quantitative reverse transcription polymerase chain reaction (qRT-PCR)-based ratio. APE1’s endonuclease activity was measured with AP-site incision assays. APE1-DROSHA interaction was studied with immunofluorescence, confocal and proximity ligation analyses. The miR-92b’s targeting of low-density lipoprotein receptor (LDLR) was investigated with luciferase reporter assays. The miR-92b mimics and shRNA-based miR-92b silencing, as well as LDLR overexpression and short interfering RNA (siRNA)-based LDLR silencing, were employed in CaSki and SiHa cervical cancer cells. Cell proliferation and chemosensitivity to paclitaxel and cisplatin were assayed. Cell-cycle progression and apoptosis were assessed by flow cytometry. Tumor growth was studied in a murine xenograft model. Results: APE1’s endonuclease activity, via association with the DROSHA-processing complex, is necessary for processing mature miR-92b, thereby regulating expression of miR-92b’s direct target LDLR. The miR-92b promotes cell proliferation in vitro and in vivo, promotes cell-cycle progression, and reduces apoptosis and chemosensitivity. LDLR silencing recapitulated miR-92b’s transformative effects, while LDLR overexpression rescued these effects. Conclusions: APE1 enhances miR-92b processing, thereby suppressing LDLR expression and enhancing cervical carcinoma progression. Our identification of the novel APE1-miR-92b-LDLR axis improves our understanding of the complex pathogenesis of cervical carcinoma and reveals a novel therapeutic strategy for combating this disease.

PAICS is related to glioma grade and can promote glioma growth and migration

“…Then, flow cytometric analysis was used to detect numbers of cell in G0‐G1, S, G2–M phases and apoptosis. 17 …”

Expression levels and clinical values of miR-92b-3p in breast cancer

“…This reveals that miR-92b-3p has a significant effect on the occurrence and development of BC. According to some studies, APE1 enhances the processing of miR-92b-3p, thus inhibiting LDLR expression and promoting the progression of cervical cancer [ 25 ]. According to independent verifications, the detection of this miRNA can identify patients with metastatic colorectal cancer who would benefit from the combined treatment of bevacizumab and oxaliplatin-based chemotherapy [ 26 ].…”

USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination

“…18,19) A variety of malignant tumors express high levels of LDLRs on their membranes, [20][21][22], including cervical cancer. 23) Therefore, LDL may be used as a carrier to obtain selective delivery of antineoplastic drugs to tumors. Although the LDL uptake by the liver, spleen, and adrenals is higher than that by tumors, the LDLR-mediated uptake by these organs may be selectively down-regulated via methods that do not affect the expression of LDLRs on tumor cells.…”