Transcriptome‑wide piRNA profiling in human gastric cancer

Lin,Xiandong; Xia,Yan; Hu,Dan; Mao,Qiao; Yu,Zongyang; Zhang,Hejun; Li,Chao; Chen,Gang; Liu,Fen; Zhu,Weifeng; Shi,Yi; Zhang,Huihao; Zheng,Jianming; Sun,Tao; Xu,Jianying; Chao,Herta   H.; Zheng,Xiongwei; Luο,Xingguang

doi:10.3892/or.2019.7073

Transcriptome‑wide piRNA profiling in human gastric cancer

Authors:
- Xiandong Lin
- Yan Xia
- Dan Hu
- Qiao Mao
- Zongyang Yu
- Hejun Zhang
- Chao Li
- Gang Chen
- Fen Liu
- Weifeng Zhu
- Yi Shi
- Huihao Zhang
- Jianming Zheng
- Tao Sun
- Jianying Xu
- Herta H. Chao
- Xiongwei Zheng
- Xingguang Luο
View Affiliations

Affiliations: Laboratory of Radiation Oncology and Radiobiology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China, Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China, People's Hospital of Deyang City, Deyang, Sichun 618000, P.R. China, Department of Medical Oncology, Fuzhou General Hospital of PLA, Fuzhou, Fujian 350025, P.R. China, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian 350014, P.R. China, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350002, P.R. China, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Huashan Hospital, Fudan University School of Medicine, Shanghai 200040, P.R. China, Zhuhai Municipal Maternal and Children's Health Hospital, Zhuhai, Guangdong 519000, P.R. China, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, P.R. China, Huilongguan Hospital, Beijing University School of Clinical Medicine, Beijing 100096, P.R. China
Published online on: March 18, 2019 https://doi.org/10.3892/or.2019.7073
Pages: 3089-3099

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Piwi‑interacting RNAs (piRNAs) comprise the largest class of non‑coding RNAs. They represent a molecular feature shared by all non‑aging biological systems, including germline and somatic cancer stem cells, which display an indefinite capacity of renewal and proliferation and are potentially immortal. They have been identified in animal stomachs, but their relationship with human gastric cancers remains largely unclear. The present study aimed to identify the piRNAs associated with human gastric cancers across the whole transcriptome. Fresh tumor tissues and adjacent non‑tumorous tissues from stomachs were examined using a piRNA microarray (23,677 piRNAs) that was then validated by qPCR. The differential expression of piRNAs between cases and controls was analyzed. The transposable elements (TEs) that are potentially targeted by the risk piRNAs were searched. The expression of the nearest genes that are complementary to the sequences of the piRNAs was examined in the stomach tissue. The regulatory effects of genome‑wide significant and replicated cancer‑risk DNA variants on the piRNA expression in stomach were tested. Based on the findings, we identified a total of 8,759 piRNAs in human stomachs. Of all, 50 were significantly (P<0.05) and differentially (>2‑fold change) expressed between the cases and controls, and 64.7% of the protein‑coding genes potentially regulated by the gastric cancer‑associated piRNAs were expressed in the human stomach. The expression of many cancer‑associated piRNAs was correlated with the genome‑wide and replicated cancer‑risk SNPs. In conclusion, we conclude that piRNAs are abundant in human stomachs and may play important roles in the etiological processes of gastric cancers.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Lin X, Hu D, Chen G, Shi Y, Zhang H, Wang X, Guo X, Lu L, Black D, Zheng XW and Luo X: Associations of THBS2 and THBS4 polymorphisms to gastric cancer in a Southeast Chinese population. Cancer Genet. 209:215–222. 2016. View Article : Google Scholar : PubMed/NCBI
3	Berger H, Marques MS, Zietlow R, Meyer TF, Machado JC and Figueiredo C: Gastric cancer pathogenesis. Helicobacter. 21 (Suppl 1):S34–S38. 2016. View Article : Google Scholar
4	Kim J, Yum S, Kang C and Kang SJ: Gene-gene interactions in gastrointestinal cancer susceptibility. Oncotarget. 7:67612–67625. 2016.PubMed/NCBI
5	Lin XD, Chen SQ, Qi YL, Zhu JW, Tang Y and Lin JY: Polymorphism of THBS1 rs1478604 A>G in 5-untranslated region is associated with lymph node metastasis of gastric cancer in a Southeast Chinese population. DNA Cell Biol. 31:511–519. 2012. View Article : Google Scholar : PubMed/NCBI
6	Nakao T, Kurita N, Komatsu M, Yoshikawa K, Iwata T, Utsunomiya T and Shimada M: Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer. Int J Clin Oncol. 16:145–152. 2011. View Article : Google Scholar : PubMed/NCBI
7	Takahata M, Inoue Y, Tsuda H, Imoto I, Koinuma D, Hayashi M, Ichikura T, Yamori T, Nagasaki K, Yoshida M, et al: SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells. J Biol Chem. 284:3334–3344. 2009. View Article : Google Scholar : PubMed/NCBI
8	Hong CS, Jeong O, Piao Z, Guo C, Jung MR, Choi C and Park YK: HOXB5 induces invasion and migration through direct transcriptional up-regulation of β-catenin in human gastric carcinoma. Biochem J. 472:393–403. 2015. View Article : Google Scholar : PubMed/NCBI
9	Xie SS, Jin J, Xu X, Zhuo W and Zhou TH: Emerging roles of non-coding RNAs in gastric cancer: Pathogenesis and clinical implications. World J Gastroenterol. 22:1213–1223. 2016. View Article : Google Scholar : PubMed/NCBI
10	Huang T, Ji Y, Hu D, Chen B, Zhang H, Li C, Chen G, Luo X, Zheng XW and Lin X: SNHG8 is identified as a key regulator of epstein-barr virus(EBV)-associated gastric cancer by an integrative analysis of lncRNA and mRNA expression. Oncotarget. 7:80990–81002. 2016. View Article : Google Scholar : PubMed/NCBI
11	Fu A, Jacobs DI, Hoffman AE, Zheng T and Zhu Y: PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome. Carcinogenesis. 36:1094–1102. 2015. View Article : Google Scholar : PubMed/NCBI
12	Cheng J, Guo JM, Xiao BX, Miao Y, Jiang Z, Zhou H and Li QN: piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells. Clin Chim Acta. 412:1621–1625. 2011. View Article : Google Scholar : PubMed/NCBI
13	Zuo L, Wang Z, Tan Y, Chen X and Luo X: piRNAs and their functions in the brain. Int J Hum Genet. 16:53–60. 2016. View Article : Google Scholar : PubMed/NCBI
14	Ross RJ, Weiner MM and Lin H: PIWI proteins and PIWI-interacting RNAs in the soma. Nature. 505:353–359. 2014. View Article : Google Scholar : PubMed/NCBI
15	Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, Morris P, Brownstein MJ, Kuramochi-Miyagawa S, Nakano T, et al: A novel class of small RNAs bind to MILI protein in mouse testes. Nature. 442:203–207. 2006. View Article : Google Scholar : PubMed/NCBI
16	Sturm Á, Perczel A, Ivics Z and Vellai T: The Piwi-piRNA pathway: Road to immortality. Aging Cell. 16:906–911. 2017. View Article : Google Scholar : PubMed/NCBI
17	Mei Y, Clark D and Mao L: Novel dimensions of piRNAs in cancer. Cancer Lett. 336:46–52. 2013. View Article : Google Scholar : PubMed/NCBI
18	Ng KW, Anderson C, Marshall EA, Minatel BC, Enfield KS, Saprunoff HL, Lam WL and Martinez VD: Piwi-interacting RNAs in cancer: Emerging functions and clinical utility. Mol Cancer. 15:52016. View Article : Google Scholar : PubMed/NCBI
19	Busch J, Ralla B, Jung M, Wotschofsky Z, Trujillo-Arribas E, Schwabe P, Kilic E, Fendler A and Jung K: Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res. 34:612015. View Article : Google Scholar : PubMed/NCBI
20	Hashim A, Rizzo F, Marchese G, Ravo M, Tarallo R, Nassa G, Giurato G, Santamaria G, Cordella A, Cantarella C and Weisz A: RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer. Oncotarget. 5:9901–9910. 2014. View Article : Google Scholar : PubMed/NCBI
21	Yan H, Wu QL, Sun CY, Ai LS, Deng J, Zhang L, Chen L, Chu ZB, Tang B, Wang K, et al: piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma. Leukemia. 29:196–206. 2015. View Article : Google Scholar : PubMed/NCBI
22	Law PT, Qin H, Ching AK, Lai KP, Co NN, He M, Lung RW, Chan AW, Chan TF and Wong N: Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol. 58:1165–1173. 2013. View Article : Google Scholar : PubMed/NCBI
23	Huang G, Hu H, Xue X, Shen S, Gao E, Guo G, Shen X and Zhang X: Altered expression of piRNAs and their relation with clinicopathologic features of breast cancer. Clin Transl Oncol. 15:563–568. 2013. View Article : Google Scholar : PubMed/NCBI
24	Zhang H, Ren Y, Xu H, Pang D, Duan C and Liu C: The expression of stem cell protein Piwil2 and piR-932 in breast cancer. Surg Oncol. 22:217–223. 2013. View Article : Google Scholar : PubMed/NCBI
25	Chu H, Hui G, Yuan L, Shi D, Wang Y, Du M, Zhong D, Ma L, Tong N, Qin C, et al: Identification of novel piRNAs in bladder cancer. Cancer Lett. 356:561–567. 2015. View Article : Google Scholar : PubMed/NCBI
26	Qiu W, Guo X, Lin X, Yang Q, Zhang W, Zhang Y, Zuo L, Zhu Y, Li CR, Ma C and Luo X: Transcriptome-wide piRNA profiling in human brains of Alzheimer's disease. Neurobiol Aging. 57:170–177. 2017. View Article : Google Scholar : PubMed/NCBI
27	Martinez VD, Enfield KSS, Rowbotham DA and Lam WL: An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence. Gastric Cancer. 19:660–665. 2016. View Article : Google Scholar : PubMed/NCBI
28	Levin HL and Moran JV: Dynamic interactions between transposable elements and their hosts. Nat Rev Genet. 12:615–627. 2011. View Article : Google Scholar : PubMed/NCBI
29	Malone CD and Hannon GJ: Small RNAs as guardians of the genome. Cell. 136:656–668. 2009. View Article : Google Scholar : PubMed/NCBI
30	Reilly MT, Faulkner GJ, Dubnau J, Ponomarev I and Gage FH: The role of transposable elements in health and diseases of the central nervous system. J Neurosci. 33:17577–17586. 2013. View Article : Google Scholar : PubMed/NCBI
31	Roy J, Sarkar A, Parida S, Ghosh Z and Mallick B: Small RNA sequencing revealed dysregulated piRNAs in Alzheimer's disease and their probable role in pathogenesis. Mol Biosyst. 13:565–576. 2017. View Article : Google Scholar : PubMed/NCBI
32	Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, Baek J, Burdette L, Chang J, Chung C, et al: Genome-wide association study of gastric adenocarcinoma in Asia: A comparison of associations between cardia and non-cardia tumours. Gut. 65:1611–1618. 2016. View Article : Google Scholar : PubMed/NCBI
33	Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Dong LM, et al: A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet. 42:764–767. 2010. View Article : Google Scholar : PubMed/NCBI
34	Wang Z, Dai J, Hu N, Miao X, Abnet CC, Yang M, Freedman ND, Chen J, Burdette L, Zhu X, et al: Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: Pooled results from two Chinese genome-wide association studies. Gut. 66:581–587. 2017. View Article : Google Scholar : PubMed/NCBI
35	Helgason H, Rafnar T, Olafsdottir HS, Jonasson JG, Sigurdsson A, Stacey SN, Jonasdottir A, Tryggvadottir L, Alexiusdottir K, Haraldsson A, et al: Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 47:906–910. 2015. View Article : Google Scholar : PubMed/NCBI
36	Shi Y, Hu Z, Wu C, Dai J, Li H, Dong J, Wang M, Miao X, Zhou Y, Lu F, et al: A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1. Nat Genet. 43:1215–1218. 2011. View Article : Google Scholar : PubMed/NCBI
37	Chen YC, Fang WL, Wang RF, Liu CA, Yang MH, Lo SS, Wu CW, Li AF, Shyr YM and Huang KH: Clinicopathological variation of lauren classification in gastric cancer. Pathol Oncol Res. 22:197–202. 2016. View Article : Google Scholar : PubMed/NCBI
38	Edge SB and Compton CC: The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
39	Lau NC, Seto AG, Kim J, Kuramochi-Miyagawa S, Nakano T, Bartel DP and Kingston RE: Characterization of the piRNA complex from rat testes. Science. 313:363–367. 2006. View Article : Google Scholar : PubMed/NCBI
40	He QQ, Xiong LL, Liu F, He X, Feng GY, Shang FF, Xia QJ, Wang YC, Qiu DL, Luo CZ, et al: MicroRNA-127 targeting of mitoNEET inhibits neurite outgrowth, induces cell apoptosis and contributes to physiological dysfunction after spinal cord transection. Sci Rep. 6:352052016. View Article : Google Scholar : PubMed/NCBI
41	Yuan JS, Reed A, Chen F and Stewart CN Jr: Statistical analysis of real-time PCR data. BMC Bioinformatics. 7:852006. View Article : Google Scholar : PubMed/NCBI
42	GTEx Consortium: The genotype-tissue expression (GTEx) project. Nat Genet. 45:580–585. 2013. View Article : Google Scholar : PubMed/NCBI
43	Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW III and Su AI: BioGPS: An extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 10:R1302009. View Article : Google Scholar : PubMed/NCBI
44	Wilhelm M, Schlegl J, Hahne H, Gholami AM, Lieberenz M, Savitski MM, Ziegler E, Butzmann L, Gessulat S, Marx H, et al: Mass-spectrometry-based draft of the human proteome. Nature. 509:582–587. 2014. View Article : Google Scholar : PubMed/NCBI
45	Ohlsson L, Hammarström ML, Lindmark G, Hammarström S and Sitohy B: Ectopic expression of the chemokine CXCL17 in colon cancer cells. Br J Cancer. 114:697–703. 2016. View Article : Google Scholar : PubMed/NCBI
46	Oosterhoff D, Overmeer RM, de Graaf M, van der Meulen IH, Giaccone G, van Beusechem VW, Haisma HJ, Pinedo HM and Gerritsen WR: Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11. Br J Cancer. 92:882–887. 2005. View Article : Google Scholar : PubMed/NCBI
47	Xie X, Li F, Zhang H, Lu Y, Lian S, Lin H, Gao Y and Jia L: EpCAM aptamer-functionalized mesoporous silica nanoparticles for efficient colon cancer cell-targeted drug delivery. Eur J Pharm Sci. 83:28–35. 2016. View Article : Google Scholar : PubMed/NCBI
48	Russo A, Maiolino S, Pagliara V, Ungaro F, Tatangelo F, Leone A, Scalia G, Budillon A, Quaglia F and Russo G: Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles. Oncotarget. 7:79670–79687. 2016. View Article : Google Scholar : PubMed/NCBI
49	Pagliara V, Saide A, Mitidieri E, d'Emmanuele di Villa Bianca R, Sorrentino R, Russo G and Russo A: 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-β-synthase in colon cancer cells lacking p53. Oncotarget. 7:50333–50348. 2016. View Article : Google Scholar : PubMed/NCBI
50	Russo A, Pagliara V, Albano F, Esposito D, Sagar V, Loreni F, Irace C, Santamaria R and Russo G: Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53. Cell Cycle. 15:41–51. 2016. View Article : Google Scholar : PubMed/NCBI
51	Wang SY, Gao K, Deng DL, Cai JJ, Xiao ZY, He LQ, Jiao HL, Ye YP, Yang RW, Li TT, et al: TLE4 promotes colorectal cancer progression through activation of JNK/c-Jun signaling pathway. Oncotarget. 7:2878–2888. 2016.PubMed/NCBI
52	Liu YL, Gao X, Jiang Y, Zhang G, Sun ZC, Cui BB and Yang YM: Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer. J Cancer Res Clin Oncol. 141:661–669. 2015. View Article : Google Scholar : PubMed/NCBI
53	Seo GS, Yu JI, Chae SC, Park WC, Shin SR, Yoo ST, Choi SC and Lee SH: EED gene polymorphism in patients with colorectal cancer. Int J Biol Markers. 28:274–279. 2013. View Article : Google Scholar : PubMed/NCBI
54	Song L, Chen X, Gao S, Zhang C, Qu C, Wang P and Liu L: Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway. Tumour Biol. Oct 12–2016.(Epub ahead of print). View Article : Google Scholar :
55	Jiang SH, He P, Ma MZ, Wang Y, Li RK, Fang F, Fu Y, Tian GA, Qin WX and Zhang ZG: PNMA1 promotes cell growth in human pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol. 7:3827–3835. 2014.PubMed/NCBI
56	Hiraoka N, Yamazaki-Itoh R, Ino Y, Mizuguchi Y, Yamada T, Hirohashi S and Kanai Y: CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis. Gastroenterology. 140:310–321. 2011. View Article : Google Scholar : PubMed/NCBI
57	Li L, Yan J, Xu J, Liu CQ, Zhen ZJ, Chen HW, Ji Y, Wu ZP, Hu JY, Zheng L and Lau WY: CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma. PLoS One. 9:e1100642014. View Article : Google Scholar : PubMed/NCBI
58	Chan AW, Tong JH, Chan SL, Lai PB and To KF: Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology. 64:935–950. 2014. View Article : Google Scholar : PubMed/NCBI
59	Kang JS: Increased expression of epithelial cell adhesion molecule (EpCAM) in rat hepatic tumors induced by diethylnitrosamine. Asian Pac J Cancer Prev. 13:3627–3630. 2012. View Article : Google Scholar : PubMed/NCBI
60	Luo J, Cai Q, Wang W, Huang H, Zeng H, He W, Deng W, Yu H, Chan E, Ng CF, et al: A microRNA-7 binding site polymorphism in HOXB5 leads to differential gene expression in bladder cancer. PLoS One. 7:e401272012. View Article : Google Scholar : PubMed/NCBI
61	Brennecke J, Aravin AA, Stark A, Dus M, Kellis M, Sachidanandam R and Hannon GJ: Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell. 128:1089–1103. 2007. View Article : Google Scholar : PubMed/NCBI
62	Burkhardt AM, Maravillas-Montero JL, Carnevale CD, Vilches-Cisneros N, Flores JP, Hevezi PA and Zlotnik A: CXCL17 is a major chemotactic factor for lung macrophages. J Immunol. 193:1468–1474. 2014. View Article : Google Scholar : PubMed/NCBI
63	Matsui A, Yokoo H, Negishi Y, Endo-Takahashi Y, Chun NA, Kadouchi I, Suzuki R, Maruyama K, Aramaki Y, Semba K, et al: CXCL17 expression by tumor cells recruits CD11b+Gr1 high F4/80- cells and promotes tumor progression. PLoS One. 7:e440802012. View Article : Google Scholar : PubMed/NCBI
64	Weinstein EJ, Head R, Griggs DW, Sun D, Evans RJ, Swearingen ML, Westlin MM and Mazzarella R: VCC-1, a novel chemokine, promotes tumor growth. Biochem Biophys Res Commun. 350:74–81. 2006. View Article : Google Scholar : PubMed/NCBI
65	Mu X, Chen Y, Wang S, Huang X, Pan H and Li M: Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai). 41:631–637. 2009. View Article : Google Scholar : PubMed/NCBI
66	Esposito T, Magliocca S, Formicola D and Gianfrancesco F: piR_015520 belongs to Piwi-associated RNAs regulates expression of the human melatonin receptor 1A gene. PLoS One. 6:e227272011. View Article : Google Scholar : PubMed/NCBI