METTL3 enhances pancreatic ductal adenocarcinoma progression and gemcitabine resistance through modifying <i>DDX23</i> mRNA N6 adenosine methylation

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Abstract

The aim of the present study was to clarify the mechanism of how METTL3 regulated pancreatic ductal adenocarcinoma (PDAC) progression by m6A modification of its downstream target mRNA and signaling pathway. Immunoblotting and qRT-PCR assays was employed to determine the expression levels of METTL3. In situ fluorescence hybridization was conducted to localize the cellular distribution of METTL3 and DEAD-box helicase 23 (DDX23). CCK8, colony formation, EDU incorporation, TUNEL, wound healing and Transwell assays were carried out accordingly to study the viability, proliferation, apoptosis, and mobility of cells under different treatments in vitro. Xenograft and animal lung metastasis experiments were also conducted to study the functional role of METTL3 or DDX23 on tumor growth and lung metastasis in vivo. MeRIP-qPCR and bioinformatical analyses were used to obtain the potential direct targets of METTL3. It was shown that m6A methyltransferase METTL3 was upregulated in PDAC tissues with gemcitabine resistance, and its knockdown sensitized pancreatic cancer cells to chemotherapy. Furthermore, silencing METTL3 remarkably reduced pancreatic cancer cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, validation experiments confirmed that DDX23 mRNA was a direct target of METTL3 in YTHDF1-dependent manner. Additionally, DDX23 silence resulted in the suppression of pancreatic cancer cell malignancy and PIAK/Akt signaling inactivation. Strikingly, rescuse experiments demonstrated the inhibitive effects of METTL3 silence on cell phenotypes and gemcitabine resistance were partially reversed by forcibly expressed DDX23. In summary, METTL3 promotes PDAC progression and gemcitabine resistance by modifying DDX23 mRNA m6A methylation and enhancing PI3K/Akt signaling activation. Our findings establish a potential tumor promotive and chemo-resistant role for METTL3/DDX23 axis in PDAC.

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Most cited references 33

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Cancer Statistics, 2021

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2021)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

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Pancreatic cancer

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Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.

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Gemcitabine resistance in pancreatic ductal adenocarcinoma.

Yoav Binenbaum, Shorook Na’ara, Ziv Gil (2015)

Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity.

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Author and article information

Contributors

Xiang Zhang: seva1101@163.com

Shangeng Weng:

ORCID: http://orcid.org/0000-0001-8802-6616

Shangeng@sina.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 28 March 2023

Publication date PMC-release: 28 March 2023

Publication date Collection: March 2023

Volume: 14

Issue: 3

Electronic Location Identifier: 221

Affiliations

[1 ]GRID grid.412683.a, ISNI 0000 0004 1758 0400, Department of Hepatopancreatobiliary Surgery, , The First Affiliated Hospital of Fujian Medical University, ; Fuzhou, Fujian 350001 China

[2 ]GRID grid.412683.a, ISNI 0000 0004 1758 0400, Fujian Abdominal Surgery Research Institute, , The First Affiliated Hospital, Fujian Medical University, ; Fuzhou, Fujian 350001 China

[3 ]GRID grid.256112.3, ISNI 0000 0004 1797 9307, National Regional Medical Center, , Binhai Campus of the First Affiliated Hospital, Fujian Medical University, ; Fuzhou, Fujian 350212 China

[4 ]GRID grid.415108.9, ISNI 0000 0004 1757 9178, Department of Oncology, , Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, ; Fuzhou, Fujian 350001 China

Author information

Chengjie Lin http://orcid.org/0000-0003-3194-0380

Shangeng Weng http://orcid.org/0000-0001-8802-6616

Article

Publisher ID: 5715

DOI: 10.1038/s41419-023-05715-1

PMC ID: 10050319

PubMed ID: 36977668

SO-VID: 16dff42d-6ed5-441d-a823-8b648c97befb

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 November 2022

Date revision received : 24 February 2023

Date accepted : 27 February 2023

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ScienceOpen disciplines: Cell biology

Keywords: cancer genetics,cell death

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ScienceOpen disciplines: Cell biology

Keywords: cancer genetics, cell death

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METTL3 enhances pancreatic ductal adenocarcinoma progression and gemcitabine resistance through modifying DDX23 mRNA N6 adenosine methylation

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Evolutionary Cell Biology

Most cited references 33

Cancer Statistics, 2021

Pancreatic cancer

Gemcitabine resistance in pancreatic ductal adenocarcinoma.

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