Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer

Sui,Minghua; Jiao,Aihong; Zhai,Huiyuan; Wang,Yan; Wang,Yong; Sun,Dengjun; Li,Peng

doi:10.3892/etm.2017.4548

Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer

Authors:
- Minghua Sui
- Aihong Jiao
- Huiyuan Zhai
- Yan Wang
- Yong Wang
- Dengjun Sun
- Peng Li
View Affiliations

Affiliations: Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264001, P.R. China, Department of Gastrointestinal Surgery, Yuhuangding Hospital, Yantai, Shandong 264001, P.R. China, Department of Hematology, Yuhuangding Hospital, Yantai, Shandong 264001, P.R. China, Department of General Surgery, General Hospital of Ping Coal Group, Pingdingshan, Henan 467000, P.R. China
Published online on: June 6, 2017 https://doi.org/10.3892/etm.2017.4548
Pages: 657-663
Copyright: © Sui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Gastric cancer is one of the most common types of human cancer associated with a poor prognosis. MicroRNAs (miRs), a class of non‑coding RNAs that are 18‑25 nucleotides in length, act as key regulators in gene expression, and have been implicated in various human cancer types. miR‑125b has been implicated in the malignant progression of gastric cancer. However, the association between miR‑125b expression, clinicopathological characteristics and trastuzumab resistance in human epidermal growth factor receptor 2 (HER2)‑positive gastric cancer remains unclear. In the current study, in situ hybridization data demonstrated that 81.8% (108/132) of gastric cancer tissues exhibited positive expression of miR‑125b, while only 26.3% (10/38) of non‑tumor gastric tissues were miR‑125b‑positive. Reverse transcription-quantitative polymerase chain reaction data indicated that the expression level of miR‑125b was markedly increased in gastric cancer tissues compared with non‑cancerous gastric tissues. Furthermore, the miR‑125b level was significantly associated with tumor (T) stage, lymph node metastasis, distant metastasis and TNM stage of gastric cancer (P<0.05). Increased miR‑125b expression predicated poor prognosis in patients with gastric cancer. For HER2‑positive gastric cancer, the upregulation of miR‑125b expression was significantly associated with advanced malignant progression, as well as a poor prognosis (P<0.05). Furthermore, data from the present study indicated that the increased miR‑125b level was significantly associated with trastuzumab resistance in HER2‑positive gastric cancer (P<0.05). Therefore, the current study suggests that miR‑125b may become a potential biomarker for predicting prognoses and clinical outcomes in patients with HER2‑positive gastric cancer that receive trastuzumab treatment.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	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
3	Li Z, Lei H, Luo M, Wang Y, Dong L, Ma Y, Liu C, Song W, Wang F, Zhang J, et al: DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer. 18:43–54. 2015. View Article : Google Scholar : PubMed/NCBI
4	Qiu T, Zhou X, Wang J, Du Y, Xu J, Huang Z, Zhu W, Shu Y and Liu P: miR-145, miR-133a and miR-133b inhibit proliferation, migration, invasion and cell cycle progression via targeting transcription factor Sp1 in gastric cancer. FEBS Lett. 588:1168–1177. 2014. View Article : Google Scholar : PubMed/NCBI
5	John B, Enright AJ, Aravin A, Tuschl T, Sander C and Marks DS: Human MicroRNA targets. PLoS Biol. 2:e3632004. View Article : Google Scholar : PubMed/NCBI
6	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
7	Lu C, Shan Z, Li C and Yang L: miR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp. Biomed Pharmacother. 86:450–456. 2017. View Article : Google Scholar : PubMed/NCBI
8	Zhang Y, Xu W, Ni P, Li A, Zhou J and Xu S: miR-99a and miR-491 regulate cisplatin resistance in human gastric cancer cells by targeting CAPNS1. Int J Biol Sci. 12:1437–1447. 2016. View Article : Google Scholar : PubMed/NCBI
9	Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M and Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:pp. 2999–3004. 2004; View Article : Google Scholar : PubMed/NCBI
10	Karbasy SH, Taheriazam A, Mirghasemi A, Sedaghati F, Shakeri M, Yahaghi E and Bahador R: RETRACTED ARTICLE: Upregulation of miR-300 and downregulation of miR-125b act as potential predictor biomarkers in progression, metastasis, and poor prognosis of osteosarcoma. Tumour Biol. 2015.(Epub ahead of print). PubMed/NCBI
11	Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, Huang MY, Hou JH, Wu QL, Zeng MS, et al: miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 71:3552–3562. 2011. View Article : Google Scholar : PubMed/NCBI
12	Guan Y, Yao H, Zheng Z, Qiu G and Sun K: miR-125b targets BCL3 and suppresses ovarian cancer proliferation. Int J Cancer. 128:2274–2283. 2011. View Article : Google Scholar : PubMed/NCBI
13	Pan S, Cheng X, Chen H, Castro PD, Ittmann MM, Hutson AW, Zapata SK and Sifers RN: ERManI is a target of miR-125b and promotes transformation phenotypes in hepatocellular carcinoma (HCC). PLoS One. 8:e728292013. View Article : Google Scholar : PubMed/NCBI
14	Nishida N, Yokobori T, Mimori K, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Kuwano H and Mori M: MicroRNA miR-125b is a prognostic marker in human colorectal cancer. Int J Oncol. 38:1437–1443. 2011.PubMed/NCBI
15	Amir S, Ma AH, Shi XB, Xue L, Kung HJ and White RW Devere: Oncomir miR-125b suppresses p14(ARF) to modulate p53-dependent and p53-independent apoptosis in prostate cancer. PLoS One. 8:e610642013. View Article : Google Scholar : PubMed/NCBI
16	Yuxia M, Zhennan T and Wei Z: Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J Cancer Res Clin Oncol. 138:2045–2050. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, et al: Relation between microRNA expression and progression and prognosis of gastric cancer: A microRNA expression analysis. Lancet Oncol. 11:136–146. 2010. View Article : Google Scholar : PubMed/NCBI
18	Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, Sun L, Ji G, Shi Y, Han Z, et al: miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 9:824–833. 2011. View Article : Google Scholar : PubMed/NCBI
19	Wu JG, Wang JJ, Jiang X, Lan JP, He XJ, Wang HJ, Ma YY, Xia YJ, Ru GQ, Ma J, et al: miR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis. Gastric Cancer. 18:729–739. 2015. View Article : Google Scholar : PubMed/NCBI
20	Fassan M, Pizzi M, Realdon S, Balistreri M, Guzzardo V, Zagonel V, Castoro C, Mastracci L, Farinati F, Nitti D, et al: The HER2-miR125a5p/miR125b loop in gastric and esophageal carcinogenesis. Hum Pathol. 44:1804–1810. 2013. View Article : Google Scholar : PubMed/NCBI
21	Jin MH, Nam AR, Park JE, Bang JH, Bang YJ and Oh DY: Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition. Mol Cancer Ther. pii:molcanther.0669.2016. 2017.
22	Sun R, Shen J, Gao Y, Zhou Y, Yu Z, Hornicek F, Kan Q and Duan Z: Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential. Oncotarget. 7:38333–38346. 2016.PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Bousquet M, Quelen C, Rosati R, Mansat-de Mas V, La Starza R, Bastard C, Lippert E, Talmant P, Lafage-Pochitaloff M, Leroux D, et al: Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J Exp Med. 205:2499–2506. 2008. View Article : Google Scholar : PubMed/NCBI
25	Chapiro E, Russell LJ, Struski S, Cavé H, Radford-Weiss I, Valle VD, Lachenaud J, Brousset P, Bernard OA, Harrison CJ and Nguyen-Khac F: A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia. 24:1362–1364. 2010. View Article : Google Scholar : PubMed/NCBI
26	Song F, Yang D, Liu B, Guo Y, Zheng H, Li L, Wang T, Yu J, Zhao Y, Niu R, et al: Integrated microRNA network analyses identify a poor-prognosis subtype of gastric cancer characterized by the miR-200 family. Clin Cancer Res. 20:878–889. 2014. View Article : Google Scholar : PubMed/NCBI
27	Berg M and Soreide K: EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: Implications for targeted therapy. Discov Med. 14:207–214. 2012.PubMed/NCBI
28	Ching CB and Hansel DE: Expanding therapeutic targets in bladder cancer: The PI3K/Akt/mTOR pathway. Lab Invest. 90:1406–1414. 2010. View Article : Google Scholar : PubMed/NCBI
29	Siegfried Z, Bonomi S, Ghigna C and Karni R: Regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing in cancer. Int J Cell Biol. 2013:5689312013. View Article : Google Scholar : PubMed/NCBI
30	Schneider MR and Yarden Y: The EGFR-HER2 module: A stem cell approach to understanding a prime target and driver of solid tumors. Oncogene. 35:2949–2960. 2016. View Article : Google Scholar : PubMed/NCBI
31	Thiel A and Ristimäki A: Targeted therapy in gastric cancer. APMIS. 123:365–372. 2015. View Article : Google Scholar : PubMed/NCBI
32	Teplinsky E and Muggia F: Targeting HER2 in ovarian and uterine cancers: Challenges and future directions. Gynecol Oncol. 135:364–370. 2014. View Article : Google Scholar : PubMed/NCBI
33	D'Amato V, Raimondo L, Formisano L, Giuliano M, De Placido S, Rosa R and Bianco R: Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev. 41:877–883. 2015. View Article : Google Scholar : PubMed/NCBI
34	Vilquin P, Donini CF, Villedieu M, Grisard E, Corbo L, Bachelot T, Vendrell JA and Cohen PA: MicroRNA-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer. Breast Cancer Res. 17:132015. View Article : Google Scholar : PubMed/NCBI
35	Yagishita S, Fujita Y, Kitazono S, Ko R, Nakadate Y, Sawada T, Kitamura Y, Shimoyama T, Maeda Y, Takahashi F, et al: Chemotherapy-regulated microRNA-125-HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small cell lung cancer. Mol Cancer Ther. 14:1414–1423. 2015. View Article : Google Scholar : PubMed/NCBI