Low Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity

Chang, Wei-Chun; Wang, Hsiao-Ching; Cheng, Wei‐Chung; Yang, Juan-Cheng; Chung, Wei-Min; Ho, Yen-Pin; Chen, Lumin; Hung, Yao-Ching; Lung, Wen

doi:10.2139/ssrn.3311843

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“…Interestingly, preliminary trans-omics data from epithelial ovarian carcinoma cells suggests that LDLR promotes cisplatin chemosensitivity via the LDLR- lysophosphotidylcholine (LPC)-family with sequence similarity 83-member B (FAM83B)- fibroblast growth factor receptors axis. 61 However, we did not investigate the mechanism underlying this phenomenon in cervical carcinoma cells. Further research is needed to investigate the mechanism(s) that may be involved in APE1-miR-92b-LDLR- mediated chemosensitivity to cisplatin and paclitaxel in cervical carcinoma cells.…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 98%