Abstract
Long noncoding RNAs (lncRNAs) are regarded as crucial regulators in tumor progression. Potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1 (KCNK15-AS1) has been confirmed to inhibit the migration and invasion of pancreatic cancer (PC) cells. However, its downstream mechanism and effect on other cellular functions in PC remain unknown. This study probed the function and potential mechanism of KCNK15-AS1 in PC cell growth. RT-qPCR and western blot were employed to measure gene expression in PC cells. ISH was applied to analyze KCNK15-AS1 expression in PC tissues. Functional assays were utilized to evaluate PC cell proliferation, apoptosis, migration and EMT. Mechanical experiments were adopted to detect gene interaction in PC cells. The obtained data indicated that KCNK15-AS1 was down-regulated in PC cells and tissues. Overexpressing KCNK15-AS1 hindered cell proliferation, migration and EMT while facilitated cell apoptosis in PC. Mechanically, alkylation repair homolog protein 5 (ALKBH5) was verified to induce m6A demethylation of KCNK15-AS1 to mediate KCNK15-AS1 up-regulation. KCNK15-AS1 combined with KCNK15 5’UTR to inhibit KCNK15 translation. Moreover, KCNK15-AS1 recruited MDM2 proto-oncogene (MDM2) to promote RE1 silencing transcription factor (REST) ubiquitination, thus transcriptionally upregulating phosphatase and tensin homolog (PTEN) to inactivate AKT pathway. In conclusion, our study first confirmed that KCNK15-AS1 hinders PC cell growth by regulating KCNK15 and PTEN, suggesting KCNK15-AS1 as a potential biomarker of PC.
Highlights
Pancreatic cancer (PC), a prevalent malignancy, is one of the top four fatal cancers worldwide [1]
Data from GEPIA 2 unveiled that low KCNK15-AS1 expression was related to short disease free survival of PC patients (Fig. 1B)
RT-qPCR analysis validated that KCNK15-AS1 was low-expressed in PC cell lines compared with human normal pancreatic ductal epithelial cell line HPDE6-C7, and MIA-PaCa-2 and BxPC-3 cells exhibited the lowest KCNK15-AS1 level (Fig. 1D)
Summary
Pancreatic cancer (PC), a prevalent malignancy, is one of the top four fatal cancers worldwide [1]. Whole genome and transcriptome sequencing technologies have gradually revealed the importance of non-coding RNAs (ncRNAs) [6]. Long non-coding RNAs (lncRNAs) are a class of ncRNAs with over 200 nucleotides in length and without protein-coding potentials [7]. LncRNAs participate in various cellular processes, such as proliferation, differentiation, and apoptosis [8], working as oncogenes or tumor suppressors in diverse cancers including PC [9]. ZEB2-AS1 accelerates PC cell growth via miR-204/HMGB1 axis [10]. GAS5 represses PC cell metastasis by sponging miR-221 to affect SOCS3 [11]. LncRNA potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1
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