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Abstract
Objective Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.
Design We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.
Results We identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A ‘writer’ complex (METTL13/METTL14/WTAP) and the m6A ‘reader’ YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.
Conclusions These findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.
- molecular biology
- cancer epidemiology
- cell migration
- pancreatic tumours
- RNA expression
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Footnotes
JT and YZ contributed equally.
Contributors XM and JC were the overall principal investigators in this study who conceived the study and obtained financial support, were responsible for the study design and supervised the entire study. JT and JC performed statistical analyses, interpreted the results and drafted the initial manuscript. JT, YZ, MR, YC, ZL, XP, DZ, PY, SN, MZ and YL performed laboratory experiments. RZ and XM were responsible for patient recruitment and sample preparation. All authors approved the final report for publication.
Funding This work is supported by National Natural Science Foundation of China NSFC-81673256, National High-Tech Research and Development Program of China 2014AA020609, Program for HUST Academic Frontier Youth Team and National Science Fund for Distinguished Young Scholars of China for Xiaoping Miao, National Program for Support of Top-notch Young Professionals and the Young Elite Scientist Sponsorship Program by CAST (2018QNRC001) for Jiang Chang.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Patient consent for publication Obtained.
Ethics approval This study was approved by the institutional review board of Huazhong University of Science and Technology (HUST).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.
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