Gene Signature and Identification of Clinical Trait-Related M A Regulators in Pancreatic Cancer

Overview

Journal Front Genet

Date 2020 Aug 6

PMID 32754191

Citations 21

Authors

Jie Hou

Zhan Wang

Hong Li

Hongzhi Zhang

Lan Luo

Affiliations

Soon will be listed here.

Abstract

Pancreatic cancer (PC) has a very poor prognosis and is usually diagnosed only at an advanced stage. The discovery of new biomarkers for PC will help in early diagnosis and a better prognosis for patients. Recently, N6-methyladenosine (mA) RNA modifications and their regulators have been implicated in the development of many cancers. To investigate the functions and mechanisms of mA modifications in the development of PC, 19 mA regulators, including mA-methyltransferases (ZC3H13, RBM15/15B, WTAP, KIAA1429, and METTL3/14), demethylases (FTO and ALKBH5), and binding proteins (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, HNRNPC, and HNRNPA2B1) were analyzed in 178 PC tissues from the cancer genome atlas (TCGA) database. The results were verified in PC cell lines Mia-PaCa-2, BXPC-3, and the control cell line HDE-CT. The mA regulators-based sample clusters were significantly related to overall survival (OS). Further, lasso regression identified a six-mA-regulator-signature prognostic model (KIAA1429, HNRNPC, METTL3, YTHDF1, IGF2BP2, and IGF2BP3). Model-based high-risk and low-risk groups were significantly correlated with OS and clinical traits (pathologic M, N, and clinical stages and vital status). The risk signature was verified as an independent prognostic marker for patients with PC. Finally, gene set enrichment analysis revealed mA regulators (KIAA1429, HNRNPC, and IGF2BP2) were related to multiple biological behaviors in PC, including adipocytokine signaling, the well vs. poorly differentiated tumor pathway, tumor metastasis pathway, epithelial mesenchymal transition pathway, gemcitabine resistance pathway, and stemness pathway. In summary, the m6A regulatory factors which related to clinical characteristics can be involved in the malignant progression of PC, and the constructed risk markers may be a promising prognostic biomarker that can guide the individualized treatment of PC patients.

Citing Articles

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References

Welinsky S, Lucas A . Familial Pancreatic Cancer and the Future of Directed Screening. Gut Liver. 2017; 11(6):761-770. PMC: 5669591. DOI: 10.5009/gnl16414. View

Alhamzawi R, Mohammad Ali H . The Bayesian adaptive lasso regression. Math Biosci. 2018; 303:75-82. DOI: 10.1016/j.mbs.2018.06.004. View

Feng Y, Li Y, Li L, Wang X, Chen Z . Identification of specific modules and significant genes associated with colon cancer by weighted gene co‑expression network analysis. Mol Med Rep. 2019; 20(1):693-700. DOI: 10.3892/mmr.2019.10295. View

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson S . Promoter-bound METTL3 maintains myeloid leukaemia by mA-dependent translation control. Nature. 2017; 552(7683):126-131. PMC: 6217924. DOI: 10.1038/nature24678. View

Koh C, Goh Y, Goh W . Atlas of quantitative single-base-resolution N-methyl-adenine methylomes. Nat Commun. 2019; 10(1):5636. PMC: 6904561. DOI: 10.1038/s41467-019-13561-z. View

Su Y, Huang J, Hu J . mA RNA Methylation Regulators Contribute to Malignant Progression and Have Clinical Prognostic Impact in Gastric Cancer. Front Oncol. 2019; 9:1038. PMC: 6813557. DOI: 10.3389/fonc.2019.01038. View

Lin X, Chai G, Wu Y, Li J, Chen F, Liu J . RNA mA methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 2019; 10(1):2065. PMC: 6502834. DOI: 10.1038/s41467-019-09865-9. View

Blum A, Wang P, Zenklusen J . SnapShot: TCGA-Analyzed Tumors. Cell. 2018; 173(2):530. DOI: 10.1016/j.cell.2018.03.059. View

He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P . ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation. Cell Physiol Biochem. 2018; 48(2):838-846. DOI: 10.1159/000491915. View

10.

Ansari D, Gustafsson A, Andersson R . Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015; 21(11):3157-65. PMC: 4363743. DOI: 10.3748/wjg.v21.i11.3157. View

11.

Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y . R-2HG Exhibits Anti-tumor Activity by Targeting FTO/mA/MYC/CEBPA Signaling. Cell. 2017; 172(1-2):90-105.e23. PMC: 5766423. DOI: 10.1016/j.cell.2017.11.031. View

12.

Zhao X, Cui L . Development and validation of a mA RNA methylation regulators-based signature for predicting the prognosis of head and neck squamous cell carcinoma. Am J Cancer Res. 2019; 9(10):2156-2169. PMC: 6834477. View

13.

Lock E, Dunson D . Bayesian consensus clustering. Bioinformatics. 2013; 29(20):2610-6. PMC: 3789539. DOI: 10.1093/bioinformatics/btt425. View

14.

Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T . The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 2018; 52(2):621-629. DOI: 10.3892/ijo.2017.4219. View

15.

Wu F, Cheng W, Zhao F, Tang M, Diao Y, Xu R . Association of N6-methyladenosine with viruses and related diseases. Virol J. 2019; 16(1):133. PMC: 6849232. DOI: 10.1186/s12985-019-1236-3. View

16.

Chen M, Nie Z, Wen X, Gao Y, Cao H, Zhang S . m6A RNA methylation regulators can contribute to malignant progression and impact the prognosis of bladder cancer. Biosci Rep. 2019; 39(12). PMC: 6923333. DOI: 10.1042/BSR20192892. View

17.

Geula S, Moshitch-Moshkovitz S, Dominissini D, AlFatah Mansour A, Kol N, Salmon-Divon M . Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science. 2015; 347(6225):1002-6. DOI: 10.1126/science.1261417. View

18.

Yang S, Wei J, Cui Y, Park G, Shah P, Deng Y . mA mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019; 10(1):2782. PMC: 6592937. DOI: 10.1038/s41467-019-10669-0. View

19.

Mohammed S, Van Buren 2nd G, Fisher W . Pancreatic cancer: advances in treatment. World J Gastroenterol. 2014; 20(28):9354-60. PMC: 4110567. DOI: 10.3748/wjg.v20.i28.9354. View

20.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View