Plasma microRNAs as potential new biomarkers for early detection of early gastric cancer
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摘要
BACKGROUND Early gastric cancer(EGC), compared with advanced gastric cancer(AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method.AIM To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs(miRNAs) in EGC and AGC and compared them with those in benign gastritis(BG).METHODSWe examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction(RT-qPCR)confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori(H. pylori)-negative gastritis(Control-1), and H. pylori-positive atrophic gastritis(Control-2).To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups.RESULTS Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis(Control-1) and H. pyloripositive atrophic gastritis(Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs,miR-7641, miR-425-5 p, miR-1180-3 p and miR-122-5 p, were used to effectively distinguish the Cancer group(EGC + AGC) from the Control group [area under the curve(AUC) = 0.799, 95% confidence interval(CI): 0.691-0.908, P < 0.001].Additionally, miR-425-5 p, miR-24-3 p, miR-1180-3 p and miR-122-5 p were utilized to distinguish EGC from the Control group(AUC = 0.829, 95%CI: 0.657-1.000, P =0.001). Moreover, the miR-24-3 p expression level in EGC was lower than that in the AGC(AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5 p expression level in EGC was significantly higher than that in AGC(AUC = 0.791,95%CI: 0.574-1.000, P = 0.024).CONCLUSION The differentially expressed circulatory plasma miR-425-5 p, miR-1180-3 p, miR-122-5 p, miR-24-3 p and miR-4632-5 p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.
BACKGROUND Early gastric cancer(EGC), compared with advanced gastric cancer(AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method.AIM To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs(miRNAs) in EGC and AGC and compared them with those in benign gastritis(BG).METHODSWe examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction(RT-qPCR)confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori(H. pylori)-negative gastritis(Control-1), and H. pylori-positive atrophic gastritis(Control-2).To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups.RESULTS Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis(Control-1) and H. pyloripositive atrophic gastritis(Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs,miR-7641, miR-425-5 p, miR-1180-3 p and miR-122-5 p, were used to effectively distinguish the Cancer group(EGC + AGC) from the Control group [area under the curve(AUC) = 0.799, 95% confidence interval(CI): 0.691-0.908, P < 0.001].Additionally, miR-425-5 p, miR-24-3 p, miR-1180-3 p and miR-122-5 p were utilized to distinguish EGC from the Control group(AUC = 0.829, 95%CI: 0.657-1.000, P =0.001). Moreover, the miR-24-3 p expression level in EGC was lower than that in the AGC(AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5 p expression level in EGC was significantly higher than that in AGC(AUC = 0.791,95%CI: 0.574-1.000, P = 0.024).CONCLUSION The differentially expressed circulatory plasma miR-425-5 p, miR-1180-3 p, miR-122-5 p, miR-24-3 p and miR-4632-5 p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.
BACKGROUND Early gastric cancer(EGC), compared with advanced gastric cancer(AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method.AIM To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs(miRNAs) in EGC and AGC and compared them with those in benign gastritis(BG).METHODSWe examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction(RT-qPCR)confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori(H. pylori)-negative gastritis(Control-1), and H. pylori-positive atrophic gastritis(Control-2).To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups.RESULTS Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis(Control-1) and H. pyloripositive atrophic gastritis(Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs,miR-7641, miR-425-5 p, miR-1180-3 p and miR-122-5 p, were used to effectively distinguish the Cancer group(EGC + AGC) from the Control group [area under the curve(AUC) = 0.799, 95% confidence interval(CI): 0.691-0.908, P < 0.001].Additionally, miR-425-5 p, miR-24-3 p, miR-1180-3 p and miR-122-5 p were utilized to distinguish EGC from the Control group(AUC = 0.829, 95%CI: 0.657-1.000, P =0.001). Moreover, the miR-24-3 p expression level in EGC was lower than that in the AGC(AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5 p expression level in EGC was significantly higher than that in AGC(AUC = 0.791,95%CI: 0.574-1.000, P = 0.024).CONCLUSION The differentially expressed circulatory plasma miR-425-5 p, miR-1180-3 p, miR-122-5 p, miR-24-3 p and miR-4632-5 p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.
引文
1 Siegel RL,Miller KD,Jemal A.Cancer statistics,2015.CA Cancer J Clin 2015;65:5-29[PMID:25559415 DOI:10.3322/caac.21254]
2 Torre LA,Bray F,Siegel RL,Ferlay J,Lortet-Tieulent J,Jemal A.Global cancer statistics,2012.CACancer J Clin 2015;65:87-108[PMID:25651787 DOI:10.3322/caac.21262]
3 Liu Y,Zhang X,Chen L,Zhao Q,Xia X.Cancer incidence and mortality in Gansu province,2012.Chin JCancer Res 2016;28:301-310[PMID:27478315 DOI:10.21147/j.issn.1000-9604.2016.03.04]
4 Yang Z,Zeng H,Xia R,Liu Q,Sun K,Zheng R,Zhang S,Xia C,Li H,Liu S,Zhang Z,Liu Y,Guo G,Song G,Zhu Y,Wu X,Song B,Liao X,Chen Y,Wei W,Zhuang G,Chen W.Annual cost of illness of stomach and esophageal cancer patients in urban and rural areas in China:A multi-center study.Chin JCancer Res 2018;30:439-448[PMID:30210224 DOI:10.21147/j.issn.1000-9604.2018.04.07]
5 Cheng G.Circulating miRNAs:roles in cancer diagnosis,prognosis and therapy.Adv Drug Deliv Rev2015;81:75-93[PMID:25220354 DOI:10.1016/j.addr.2014.09.001]
6 Schwarzenbach H,Nishida N,Calin GA,Pantel K.Clinical relevance of circulating cell-free microRNAs in cancer.Nat Rev Clin Oncol 2014;11:145-156[PMID:24492836 DOI:10.1038/nrclinonc.2014.5]
7 Tsujiura M,Ichikawa D,Konishi H,Komatsu S,Shiozaki A,Otsuji E.Liquid biopsy of gastric cancer patients:circulating tumor cells and cell-free nucleic acids.World J Gastroenterol 2014;20:3265-3286[PMID:24696609 DOI:10.3748/wjg.v20.i12.3265]
8 Li X,Luo F,Li Q,Xu M,Feng D,Zhang G,Wu W.Identification of new aberrantly expressed miRNAs in intestinal-type gastric cancer and its clinical significance.Oncol Rep 2011;26:1431-1439[PMID:21874264 DOI:10.3892/or.2011.1437]
9 Tsai MM,Wang CS,Tsai CY,Huang CG,Lee KF,Huang HW,Lin YH,Chi HC,Kuo LM,Lu PH,Lin KH.Circulating microRNA-196a/b are novel biomarkers associated with metastatic gastric cancer.Eur JCancer 2016;64:137-148[PMID:27420607 DOI:10.1016/j.ejca.2016.05.007]
10 Fang Y,Shen H,Li H,Cao Y,Qin R,Long L,Zhu X,Xie C,Xu W.miR-106a confers cisplatin resistance by regulating PTEN/Akt pathway in gastric cancer cells.Acta Biochim Biophys Sin(Shanghai)2013;45:963-972[PMID:24108762 DOI:10.1093/abbs/gmt106]
11 Zhou X,Zhu W,Li H,Wen W,Cheng W,Wang F,Wu Y,Qi L,Fan Y,Chen Y,Ding Y,Xu J,Qian J,Huang Z,Wang T,Zhu D,Shu Y,Liu P.Diagnostic value of a plasma microRNA signature in gastric cancer:a microRNA expression analysis.Sci Rep 2015;5:11251[PMID:26059512 DOI:10.1038/srep11251]
12 Jiang Z,Guo J,Xiao B,Miao Y,Huang R,Li D,Zhang Y.Increased expression of miR-421 in human gastric carcinoma and its clinical association.J Gastroenterol 2010;45:17-23[PMID:19802518 DOI:10.1007/s00535-009-0135-6]
13 Bibi F,Naseer MI,Alvi SA,Yasir M,Jiman-Fatani AA,Sawan A,Abuzenadah AM,Al-Qahtani MH,Azhar EI.microRNA analysis of gastric cancer patients from Saudi Arabian population.BMC Genomics2016;17:751[PMID:27766962 DOI:10.1186/s12864-016-3090-7]
14 Li C,Li JF,Cai Q,Qiu QQ,Yan M,Liu BY,Zhu ZG.MiRNA-199a-3p:A potential circulating diagnostic biomarker for early gastric cancer.J Surg Oncol 2013;108:89-92[PMID:23733518 DOI:10.1002/jso.23358]
15 Matsuzaki J,Ochiya T.Circulating microRNAs and extracellular vesicles as potential cancer biomarkers:a systematic review.Int J Clin Oncol 2017;22:413-420[PMID:28243946 DOI:10.1007/s10147-017-1104-3]
16 Zhang Z,Li Y,Fan L,Zhao Q,Tan B,Li Z,Zang A.microRNA-425-5p is upregulated in human gastric cancer and contributes to invasion and metastasis in vitro and in vivo.Exp Ther Med 2015;9:1617-1622[PMID:26136868 DOI:10.3892/etm.2015.2318]
17 Zhang Z,Wen M,Guo J,Shi J,Wang Z,Tan B,Zhang G,Zheng X,Zhang A.Clinical value of miR-425-5p detection and its association with cell proliferation and apoptosis of gastric cancer.Pathol Res Pract2017;213:929-937[PMID:28647207 DOI:10.1016/j.prp.2017.05.009]
18 Yan YF,Gong FM,Wang BS,Zheng W.MiR-425-5p promotes tumor progression via modulation of CYLD in gastric cancer.Eur Rev Med Pharmacol Sci 2017;21:2130-2136[PMID:28537672]
19 Chen Z,Ju H,Yu S,Zhao T,Jing X,Li P,Jia J,Li N,Tan B,Li Y.Prader-Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of miR-425-5p.Clin Sci(Lond)2018;132:1003-1019[PMID:29535266 DOI:10.1042/CS20171588]
20 Xu X,Gao F,Wang J,Tao L,Ye J,Ding L,Ji W,Chen X.MiR-122-5p inhibits cell migration and invasion in gastric cancer by down-regulating DUSP4.Cancer Biol Ther 2018;19:427-435[PMID:29509059 DOI:10.1080/15384047.2018.1423925]
21 Pei ZJ,Zhang ZG,Hu AX,Yang F,Gai Y.miR-122-5p inhibits tumor cell proliferation and induces apoptosis by targeting MYC in gastric cancer cells.Pharmazie 2017;72:344-347[PMID:29442023 DOI:10.1691/ph.2017.6404]
22 Li Q,Wang N,Wei H,Li C,Wu J,Yang G.miR-24-3p Regulates Progression of Gastric Mucosal Lesions and Suppresses Proliferation and Invasiveness of N87 Via Peroxiredoxin 6.Dig Dis Sci 2016;61:3486-3497[PMID:27743162 DOI:10.1007/s10620-016-4309-9]
2 Torre LA,Bray F,Siegel RL,Ferlay J,Lortet-Tieulent J,Jemal A.Global cancer statistics,2012.CACancer J Clin 2015;65:87-108[PMID:25651787 DOI:10.3322/caac.21262]
3 Liu Y,Zhang X,Chen L,Zhao Q,Xia X.Cancer incidence and mortality in Gansu province,2012.Chin JCancer Res 2016;28:301-310[PMID:27478315 DOI:10.21147/j.issn.1000-9604.2016.03.04]
4 Yang Z,Zeng H,Xia R,Liu Q,Sun K,Zheng R,Zhang S,Xia C,Li H,Liu S,Zhang Z,Liu Y,Guo G,Song G,Zhu Y,Wu X,Song B,Liao X,Chen Y,Wei W,Zhuang G,Chen W.Annual cost of illness of stomach and esophageal cancer patients in urban and rural areas in China:A multi-center study.Chin JCancer Res 2018;30:439-448[PMID:30210224 DOI:10.21147/j.issn.1000-9604.2018.04.07]
5 Cheng G.Circulating miRNAs:roles in cancer diagnosis,prognosis and therapy.Adv Drug Deliv Rev2015;81:75-93[PMID:25220354 DOI:10.1016/j.addr.2014.09.001]
6 Schwarzenbach H,Nishida N,Calin GA,Pantel K.Clinical relevance of circulating cell-free microRNAs in cancer.Nat Rev Clin Oncol 2014;11:145-156[PMID:24492836 DOI:10.1038/nrclinonc.2014.5]
7 Tsujiura M,Ichikawa D,Konishi H,Komatsu S,Shiozaki A,Otsuji E.Liquid biopsy of gastric cancer patients:circulating tumor cells and cell-free nucleic acids.World J Gastroenterol 2014;20:3265-3286[PMID:24696609 DOI:10.3748/wjg.v20.i12.3265]
8 Li X,Luo F,Li Q,Xu M,Feng D,Zhang G,Wu W.Identification of new aberrantly expressed miRNAs in intestinal-type gastric cancer and its clinical significance.Oncol Rep 2011;26:1431-1439[PMID:21874264 DOI:10.3892/or.2011.1437]
9 Tsai MM,Wang CS,Tsai CY,Huang CG,Lee KF,Huang HW,Lin YH,Chi HC,Kuo LM,Lu PH,Lin KH.Circulating microRNA-196a/b are novel biomarkers associated with metastatic gastric cancer.Eur JCancer 2016;64:137-148[PMID:27420607 DOI:10.1016/j.ejca.2016.05.007]
10 Fang Y,Shen H,Li H,Cao Y,Qin R,Long L,Zhu X,Xie C,Xu W.miR-106a confers cisplatin resistance by regulating PTEN/Akt pathway in gastric cancer cells.Acta Biochim Biophys Sin(Shanghai)2013;45:963-972[PMID:24108762 DOI:10.1093/abbs/gmt106]
11 Zhou X,Zhu W,Li H,Wen W,Cheng W,Wang F,Wu Y,Qi L,Fan Y,Chen Y,Ding Y,Xu J,Qian J,Huang Z,Wang T,Zhu D,Shu Y,Liu P.Diagnostic value of a plasma microRNA signature in gastric cancer:a microRNA expression analysis.Sci Rep 2015;5:11251[PMID:26059512 DOI:10.1038/srep11251]
12 Jiang Z,Guo J,Xiao B,Miao Y,Huang R,Li D,Zhang Y.Increased expression of miR-421 in human gastric carcinoma and its clinical association.J Gastroenterol 2010;45:17-23[PMID:19802518 DOI:10.1007/s00535-009-0135-6]
13 Bibi F,Naseer MI,Alvi SA,Yasir M,Jiman-Fatani AA,Sawan A,Abuzenadah AM,Al-Qahtani MH,Azhar EI.microRNA analysis of gastric cancer patients from Saudi Arabian population.BMC Genomics2016;17:751[PMID:27766962 DOI:10.1186/s12864-016-3090-7]
14 Li C,Li JF,Cai Q,Qiu QQ,Yan M,Liu BY,Zhu ZG.MiRNA-199a-3p:A potential circulating diagnostic biomarker for early gastric cancer.J Surg Oncol 2013;108:89-92[PMID:23733518 DOI:10.1002/jso.23358]
15 Matsuzaki J,Ochiya T.Circulating microRNAs and extracellular vesicles as potential cancer biomarkers:a systematic review.Int J Clin Oncol 2017;22:413-420[PMID:28243946 DOI:10.1007/s10147-017-1104-3]
16 Zhang Z,Li Y,Fan L,Zhao Q,Tan B,Li Z,Zang A.microRNA-425-5p is upregulated in human gastric cancer and contributes to invasion and metastasis in vitro and in vivo.Exp Ther Med 2015;9:1617-1622[PMID:26136868 DOI:10.3892/etm.2015.2318]
17 Zhang Z,Wen M,Guo J,Shi J,Wang Z,Tan B,Zhang G,Zheng X,Zhang A.Clinical value of miR-425-5p detection and its association with cell proliferation and apoptosis of gastric cancer.Pathol Res Pract2017;213:929-937[PMID:28647207 DOI:10.1016/j.prp.2017.05.009]
18 Yan YF,Gong FM,Wang BS,Zheng W.MiR-425-5p promotes tumor progression via modulation of CYLD in gastric cancer.Eur Rev Med Pharmacol Sci 2017;21:2130-2136[PMID:28537672]
19 Chen Z,Ju H,Yu S,Zhao T,Jing X,Li P,Jia J,Li N,Tan B,Li Y.Prader-Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of miR-425-5p.Clin Sci(Lond)2018;132:1003-1019[PMID:29535266 DOI:10.1042/CS20171588]
20 Xu X,Gao F,Wang J,Tao L,Ye J,Ding L,Ji W,Chen X.MiR-122-5p inhibits cell migration and invasion in gastric cancer by down-regulating DUSP4.Cancer Biol Ther 2018;19:427-435[PMID:29509059 DOI:10.1080/15384047.2018.1423925]
21 Pei ZJ,Zhang ZG,Hu AX,Yang F,Gai Y.miR-122-5p inhibits tumor cell proliferation and induces apoptosis by targeting MYC in gastric cancer cells.Pharmazie 2017;72:344-347[PMID:29442023 DOI:10.1691/ph.2017.6404]
22 Li Q,Wang N,Wei H,Li C,Wu J,Yang G.miR-24-3p Regulates Progression of Gastric Mucosal Lesions and Suppresses Proliferation and Invasiveness of N87 Via Peroxiredoxin 6.Dig Dis Sci 2016;61:3486-3497[PMID:27743162 DOI:10.1007/s10620-016-4309-9]