Role of miR-196 and its target gene HoxB8 in the development and proliferation of human colorectal cancer and the impact of neoadjuvant chemotherapy with FOLFOX4 on their expression

Shen,Songfei; Pan,Jie; Lu,Xingrong; Chi,Pan

doi:10.3892/ol.2016.5210

Role of miR-196 and its target gene HoxB8 in the development and proliferation of human colorectal cancer and the impact of neoadjuvant chemotherapy with FOLFOX4 on their expression

Authors:
- Songfei Shen
- Jie Pan
- Xingrong Lu
- Pan Chi
View Affiliations

Affiliations: Department of Medical Oncology, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: September 29, 2016 https://doi.org/10.3892/ol.2016.5210
Pages: 4041-4047

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

The present study aimed to investigate the interaction between miR-196 and its target gene homeobox B8 (HoxB8) in colorectal cancer (CRC) cells, and the sensitivity of miR‑196 and HoxB8 to fluorouracil, leucovorin and oxaliplatin (FOLFOX4) chemotherapy (1,200 mg/m2 fluorouracil, 200 mg/m2 leucovorin and 85 mg/m2 oxaliplatin). In total, 80 tissue samples were collected in the present study. In total, 50 patients undergoing preoperative chemotherapy completed at least 3 cycles (2 weeks per cycle) of 85 mg/m2 oxaliplatin (day 1) combined with a 2 h injection of 200 mg/m2 leucovorin (days 1 and 2), a bolus injection of 400 mg/m2 and 44 h continuous intravenous infusion of 1,200 mg/m2 fluorouracil. Complete response and partial response were included in the chemotherapy sensitive group (25 patients), and stable disease and progressive disease were included in the chemotherapy resistant group (25 patients). In addition, 30 patients without preoperative chemotherapy were examined for mRNA and protein expression of miR-196 and HoxB8. The expression of the mRNA and protein of miR‑196 and HoxB8 was analyzed in 30 CRC and normal mucosa tissue samples. In addition, the expression of the mRNA and protein of miR‑196 and HoxB8 was measured in 50 tissue samples obtained from patients that had received FOLFOX4 neoadjuvant chemotherapy. The expression levels of miR‑196 and HoxB8 mRNA in CRC tissues were significantly increased compared with the corresponding normal mucosa tissue (P<0.05). The miR‑196 mRNA was significantly correlated with lymph node metastasis, tumor stage and distant metastasis (P<0.05). miR‑196 was indicated to be negatively correlated with HoxB8 mRNA expression (r=‑0.458; P<0.05). The relative amount of miR‑196 in the chemotherapy‑sensitive group of patients was 0.949±0.691, which was increased compared with the chemotherapy‑resistant group (0.345±0.536; P<0.01). The relative level of HoxB8 mRNA in the chemotherapy-sensitive group was 0.490±0.372, which was decreaesd compared with the chemotherapy‑resistant group (0.725±0.438; P<0.05). HoxB8 protein expression level in the chemotherapy-sensitive group was decreased compared with the chemotherapy‑resistant group (Z=‑2.396; P=0.017). Overall, miR‑196 was correlated with metastasis and prognosis, and HoxB8 was highly expressed in CRC tissues. The difference in the gene expression of miR‑196 and HoxB8 may be associated with the sensitivity to FOLFOX4 for CRC patients. In addition, the highly expressed miR‑196 increased the sensitivity of CRC cells to chemotherapy with FOLFOX4 by inhibiting HoxB8.

View Figures

View References

1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
3	Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
4	Simpson LJ and Ansel KM: MicroRNA regulation of lymphocyte tolerance and autoimmunity. J Clin Invest. 125:2242–2249. 2015. View Article : Google Scholar : PubMed/NCBI
5	Yekta S, Shih IH and Bartel DP: MicroRNA-directed cleavage of HOXB8 mRNA. Science. 304:594–596. 2004. View Article : Google Scholar : PubMed/NCBI
6	Braig S, Mueller DW, Rothhammer T and Bosserhoff AK: MicroRNA miR-196a is a central regulator of HOX-B7 and BMP4 expression in malignant melanoma. Cell Mol Life Sci. 67:3535–3548. 2010. View Article : Google Scholar : PubMed/NCBI
7	Li Y, Zhang M, Chen H, Dong Z, Ganapathy V, Thangaraju M and Huang S: Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis. Cancer Res. 70:7894–7904. 2010. View Article : Google Scholar : PubMed/NCBI
8	Yang G, Han D, Chen X, et al: MiR-196a exerts its oncogenic effect in glioblastoma multiforme by inhibition of IκBα both in vitro and in vivo. Neuro Oncol. 16:652–661. 2014. View Article : Google Scholar : PubMed/NCBI
9	Huang F, Tang J, Zhuang X, Zhuang Y, Cheng W, Chen W, Yao H and Zhang S: MiR-196a promotes pancreatic cancer progression by targeting nuclear factor kappa-B-inhibitor alpha. PLoS One. 9:e878972014. View Article : Google Scholar : PubMed/NCBI
10	Zheng T, Wang J, Chen X and Liu L: Role of microRNA in anticancer drug resistance. Int J Cancer. 126:2–10. 2010. View Article : Google Scholar : PubMed/NCBI
11	Edge SB and Compton C: The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:143–164. 2010. View Article : Google Scholar
12	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
13	Kojima A, Uchida I, Sekizaki T, Sasaki Y, Ogikubo Y and Tamura Y: Rapid detection and identification of Clostridium chauvoei by PCR based on flagellin gene sequence. Vet Microbiol. 78:363–371. 2001. View Article : Google Scholar : PubMed/NCBI
14	Qiu JY, Liu P, Shi C and Han B: Low-grade myofibroblastic sarcomas of the maxilla. Oncol Lett. 9:619–625. 2015.PubMed/NCBI
15	Salmanidis M, Brumatti G, Narayan N, Green BD, van den Bergen JA, Sandow JJ, Bert AG, Silke N, Sladic R, Puthalakath H, et al: Hoxb8 regulates expression of microRNAs to control cell death and differentiation. Cell Death Differ. 20:1370–1380. 2013. View Article : Google Scholar : PubMed/NCBI
16	Blenkiron C and Miska EA: miRNAs in cancer: Approaches, aetiology, diagnostics and therapy. Hum Mol Genet. 16:R106–R113. 2007. View Article : Google Scholar : PubMed/NCBI
17	Urbich C, Kuehbacher A and Dimmeler S: Role of microRNAs in vascular diseases, inflammation and angiogenesis. Cardiovasc Res. 79:581–588. 2008. View Article : Google Scholar : PubMed/NCBI
18	Stark A, Brennecke J, Bushati N, Russell RB and Cohen SM: Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell. 123:1133–1146. 2005. View Article : Google Scholar : PubMed/NCBI
19	Carrington JC and Ambros V: Role of microRNAs in plant and animal development. Science. 301:336–338. 2003. View Article : Google Scholar : PubMed/NCBI
20	Akao Y, Nakagawa Y and Naoe T: Let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 29:903–906. 2006. View Article : Google Scholar : PubMed/NCBI
21	Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y and Takahashi T: A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65:9628–9632. 2005. View Article : Google Scholar : PubMed/NCBI
22	Schimanski CC, Frerichs K, Rahman F, Berger M, Lang H, Galle PR, Moehler M and Gockel I: High miR-196a levels promote the oncogenic phenotype of colorectal cancer cells. World J Gastroenterol. 15:2089–2096. 2009. View Article : Google Scholar : PubMed/NCBI
23	Chopra VS and Mishra RK: ‘Mir’acles in hox gene regulation. Bioessays. 28:445–448. 2006. View Article : Google Scholar : PubMed/NCBI
24	Zhao Z, Boyle TJ, Liu Z, Murray JI, Wood WB and Waterston RH: A negative regulatory loop between microRNA and Hox gene controls posterior identities in Caenorhabditis elegans. PLoS Genet. 6:e10010892010. View Article : Google Scholar : PubMed/NCBI
25	Tsai KW, Hu LY, Wu CW, Li SC, Lai CH, Kao HW, Fang WL and Lin WC: Epigenetic regulation of miR-196b expression in gastric cancer. Genes Chromosomes Cancer. 49:969–980. 2010. View Article : Google Scholar : PubMed/NCBI
26	Liao YL, Hu LY, Tsai KW, Wu CW, Chan WC, Li SC, Lai CH, Ho MR, Fang WL, Huang KH and Lin WC: Transcriptional regulation of miR-196b by ETS2 in gastric cancer cells. Carcinogenesis. 33:760–769. 2012. View Article : Google Scholar : PubMed/NCBI
27	Guan Y, Mizoguchi M, Yoshimoto K, Hata N, Shono T, Suzuki SO, Araki Y, Kuga D, Nakamizo A, Amano T, et al: MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance. Clin Cancer Res. 16:4289–4297. 2010. View Article : Google Scholar : PubMed/NCBI
28	National Comprehensive Cancer Network, . Clinical Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colonAugust 2–2014
29	Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT, Jiang J, Schmittgen TD and Patel T: Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology. 130:2113–2129. 2006. View Article : Google Scholar : PubMed/NCBI
30	Yue Y, Farcas R, Thiel G, Bommer C, Grossmann B, Galetzka D, Kelbova C, Küpferling P, Daser A, Zechner U and Haaf T: De novo t(12;17) (p13.3;q21.3) translocation with a breakpoint near the 5′end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations. Eur J Hum Genet. 15:570–577. 2007. View Article : Google Scholar : PubMed/NCBI
31	Hornstein E, Mansfield JH, Yekta S, Hu JK, Harfe BD, McManus MT, Baskerville S, Bartel DP and Tabin CJ: The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature. 438:671–674. 2005. View Article : Google Scholar : PubMed/NCBI
32	Rawat VP, Thoene S, Naidu VM, Arseni N, Heilmeier B, Metzeler K, Petropoulos K, Deshpande A, Quintanilla-Martinez L, Bohlander SK, et al: Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia. Blood. 111:309–319. 2008. View Article : Google Scholar : PubMed/NCBI
33	Vider BZ, Zimber A, Hirsch D, Estlein D, Chastre E, Prevot S, Gespach C, Yaniv A and Gazit A: Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun. 232:742–748. 1997. View Article : Google Scholar : PubMed/NCBI
34	Vider BZ, Zimber A, Chastre E, Gespach C, Halperin M, Mashiah P, Yaniv A and Gazit A: Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9 and Cdx-1, in human colon cancer cell lines. Biochem Biophys Res Commun. 272:513–518. 2000. View Article : Google Scholar : PubMed/NCBI
35	Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z and Huang S: Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis. Cancer Biother Radiopharm. 28:552–558. 2013. View Article : Google Scholar : PubMed/NCBI
36	Kawasaki H and Taira K: MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells. Nucleic Acids Symposium. 48:211–212. 2004. View Article : Google Scholar