N(6)-methyladenosine-mediated miR-380-3p maturation and upregulation promotes cancer aggressiveness in pancreatic cancer

ABSTRACT

N(6)-methyladenosine (m6A)-modified microRNAs (miRNAs) are relevant to cancer progression. Also, although the involvement of miR-380-3p in regulating cancer progression in bladder cancer and neuroblastoma has been preliminarily explored, its role in other types of cancer, such as pancreatic cancer (PC), has not been studied. Thus, this study aimed to investigate the role of miR-380-3p in regulating PC progression. Here, through performing Real-Time qPCR, we evidenced that miR-380-3p was significantly upregulated in the clinical pancreatic cancer tissues and cells compared to their normal counterparts. Interestingly, miR-380-3p was enriched with m6A modifications, and elimination of m6A modifications by deleting METTL3 and METTL14 synergistically suppressed miR-380-3p expressions in PC cells. Next, the gain and loss-of-function experiments verified that knockdown of miR-380-3p suppressed cell proliferation, epithelial–mesenchymal transition (EMT), and tumorigenesis in PC cells in vitro and in vivo, whereas miR-380-3p overexpression had opposite effects. Furthermore, the underlying mechanisms were uncovered, and our data suggested that miR-380-3p targeted the 3’ untranslated regions (3ʹUTRs) of PTEN for its inhibition and degradation, resulting in the activation of the downstream Akt signal pathway. Moreover, the rescuing experiments validated that both PTEN overexpression and Akt pathway inhibitor LY294002 abrogated the promoting effects of miR-380-3p overexpression on cancer aggressiveness in PC cells. Collectively, this study firstly investigated the role of the m6A-associated miR-380-3p/PTEN/Akt pathway in regulating PC progression, which provided novel therapeutic and diagnostic biomarkers for this cancer.

GRAPHICAL ABSTRACT

KEYWORDS:

• Pancreatic cancer
• miR-380-3p
• PTEN
• PI3K/Akt pathway
• cancer malignancy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Consent to participate and for publication

All the co-authors agreed to publish the final version of this manuscript.

Authors’ contributions

Zhijia Jiang and Xiaomeng Song are co-first authors, they are responsible for the conception, investigations, and manuscript drafting. Yaqing Wei, Yanxun Li, and Degang Kong are co-authors, they provide technical supports and help to collect and analyze the data. Jinjin Sun proofread and submitted this manuscript for publication.

Availability of data and material

All the data have been included in the manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21655979.2022.2088497

Additional information

Funding

This work was supported by the Youth Research Fund of the Second Hospital of Tianjin Medical University (2020ydey15).