miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis

Su, Xiaowen; Lai, Tiantian; Tao, Yue; Zhang, Yong; Zhao, Changyong; Zhou, Junjing; Chen, Enhong; Zhu, Maoqun; Zhang, Shuo; Wang, Bei; Mao, Yong; Hu, Hao

doi:10.1038/s41598-023-39506-7

Cited by 9 publications

(3 citation statements)

References 32 publications

(29 reference statements)

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“…Consistently, AHNAK2, a protein which was previously proposed as a PDAC prognosis marker with unknown function 35 , 36 , was positive in tumor area of 25/28 patients, compared with only 1/28 patients positive at adjacent normal area (X-squared = 37.979, degree of freedom = 1, p value = 7.1 × 10 −10 ). AREG, a member in EGF signaling which negatively correlates with PDAC prognosis 37 , was positive in tumor area of 18/28 patients, compared with 9/28 patients positive at adjacent normal area (X-squared = 4.5773, degree of freedom = 1, p value = 0.0324). Taken together, these data confirmed the high expression profile of tested genes in both our early PDAC-like cells as well as advanced clinical PDAC samples, demonstrating their potential as biomarkers for PDAC early detection, possibly when used as a gene panel.…”

Section: Resultsmentioning

confidence: 95%

Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

Xu,

Nipper,

Dominguez

et al. 2024

Nat Commun

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Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers.

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Section: Resultsmentioning

confidence: 95%

Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

Xu,

Nipper,

Dominguez

et al. 2024

Nat Commun

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“…EMT plays an important role in cell embryonic development, organ differentiation, wound healing, and tumor metastasis [ 29 ]. Invasion and metastasis of pancreatic cancer are closely related to EMT [ 30 – 33 ]. Activation of the EGFR/MAPK/mTOR/AKT/ERK1/2 signaling pathway has been reported to promote cancer cell growth, survival, and metabolism [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway

Zhou,

Wang,

Zhao

et al. 2024

World J Surg Onc

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Background Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated. Methods We initially conducted an analysis of the B7 family members’ expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored. Results Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs). Conclusion The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.

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“…This adds to the complexity of molecular interactions between m6A and miRNAs. miR-33a, that acts as a tumor suppressor in several cancers (137)(138)(139) inhibits the proliferation and migration of cancer cells by targeting the 3′-UTR of METTL3, thus reducing the expression of METTL3 (140,141). In addition to METTL3, other regulators of m6A dynamics are also targeted by various miRNAs in cancer (142)(143)(144)(145).…”

Section: Mirnasmentioning

confidence: 99%

Ramifications of m6A Modification on ncRNAs in Cancer

Mehmood

2023

Preprint

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N6-methyladenosine (m6A) is an RNA modification wherein N6-position of adenosine is methylated. It is one of the most prevalent internal modifications on RNA and regulates various aspects of RNA metabolism. M6A is deposited by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which modulate splicing, export, translation and stability of the modified mRNA. Recently evidence suggests that various classes of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), circular RNAs (circRNAs), and long con-coding RNAs (lncRNAs) are also targeted by this modification. Depending on the ncRNA species, m6A may affect processing, stability, or localization of these molecules. The m6A modified ncRNAs are implicated in a number of diseases including cancer. In this review, I summarize the role of m6A modification in the regulation and function of ncRNAs in tumor development. Moreover, the potential applications in cancer prognosis and therapeutics is discussed.

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miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis

Cited by 9 publications

References 32 publications

Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway

Ramifications of m6A Modification on ncRNAs in Cancer

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