Plasma exosomal microRNA‑125b as a monitoring biomarker of resistance to mFOLFOX6‑based chemotherapy in advanced and recurrent colorectal cancer patients

Yagi,Takahiro; Iinuma,Hisae; Hayama,Tamuro; Matsuda,Keiji; Nozawa,Keijirou; Tsukamoto,Mitsuo; Shimada,Ryu; Akahane,Takuya; Tsuchiya,Takeshi; Ozawa,Tsuyoshi; Hashiguchi,Yojiro

doi:10.3892/mco.2019.1911

Plasma exosomal microRNA‑125b as a monitoring biomarker of resistance to mFOLFOX6‑based chemotherapy in advanced and recurrent colorectal cancer patients

Authors:
- Takahiro Yagi
- Hisae Iinuma
- Tamuro Hayama
- Keiji Matsuda
- Keijirou Nozawa
- Mitsuo Tsukamoto
- Ryu Shimada
- Takuya Akahane
- Takeshi Tsuchiya
- Tsuyoshi Ozawa
- Yojiro Hashiguchi
View Affiliations

Affiliations: Department of Surgery, Teikyo University School of Medicine, Tokyo 173‑0003, Japan
Published online on: August 14, 2019 https://doi.org/10.3892/mco.2019.1911
Pages: 416-424

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

Liquid biomarkers for the early detection of resistance to chemotherapy are important for improving prognosis. This study investigated the usefulness of plasma exosomal microRNA‑125b (ex‑miRNA‑125b) for the early detection of resistance to modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)‑based first‑line chemotherapy in patients with advanced or recurrent (advanced/recurrent) colorectal cancer (CRC). First, ex‑miRNAs associated with resistance to mFOLFOX6‑based chemotherapy were profiled via miRNA microarray analysis. In this analysis, ex‑miR‑125b exhibited the greatest upregulation in patients with progressive disease (PD) compared with the findings for patients with stable disease (SD) and healthy controls. Next, another 55 patients with advanced/recurrent CRC who received mFOLFOX6‑based first‑line chemotherapy underwent a validation study of ex‑miR‑125b. Blood samples were collected before and during treatment until tumor progression. Ex‑miRNA levels were measured via TaqMan microRNA assays. Patients with CRC had significantly higher ex‑miR‑125b levels than healthy controls. In patients with partial responses, ex‑miR‑125b levels at the Response Evaluation Criteria in Solid Tumors (RECIST) judgment point were significantly lower than those measured before treatment. In patients with SD, ex‑miR‑125b levels did not differ before and during treatment. In patients with PD, ex‑miR‑125b levels at the RECIST judgment point were significantly higher than those measured before treatment. These changes in ex‑miR‑125b levels were significantly different between groups even 1 month after the initiation of chemotherapy. Progression‑free survival (PFS) was significantly worse in patients with high baseline ex‑miR‑125b levels than in those with low levels. In the Cox analysis, baseline ex‑miR‑125b levels and KRAS mutation were indicated to be independent prognostic factors for PFS. The present results suggest that plasma ex‑miR‑125b levels may be useful for the early detection of resistance to mFOLFOX6‑based first‑line chemotherapy. Furthermore, ex‑miR‑125b before chemotherapy is a predictive biomarker for PFS in patients with advanced/recurrent CRC.

View Figures

View References

1	Global Burden of Disease Cancer Collaboration, ; Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, Allen C, Alsharif U, Alvis-Guzman N, Amini E, et al: Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 4:1553–1568. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS and Sung JJ: Differential expression of microRNAs in plasma of patients with colorectal cancer: A potential marker for colorectal cancer screening. Gut. 58:1375–1381. 2009. View Article : Google Scholar : PubMed/NCBI
3	Huang Z, Huang D, Ni S, Peng Z, Sheng W and Du X: Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 127:118–126. 2010. View Article : Google Scholar : PubMed/NCBI
4	Wang Q, Huang Z, Ni S, Xiao X, Xu Q, Wang L, Huang D, Tan C, Sheng W and Du X: Plasma miR-601 and miR-760 are novel biomarkers for the early detection of colorectal cancer. PLoS One. 7:e443982012. View Article : Google Scholar : PubMed/NCBI
5	Kanaan Z, Rai SN, Eichenberger MR, Roberts H, Keskey B, Pan J and Galandiuk S: Plasma miR-21: A potential diagnostic marker of colorectal cancer. Ann Surg. 256:544–551. 2012. View Article : Google Scholar : PubMed/NCBI
6	Giráldez MD, Lozano JJ, Ramírez G, Hijona E, Bujanda L, Castells A and Gironella M: Circulating microRNAs as biomarkers of colorectal cancer: Results from a genome-wide profiling and validation study. Clin Gastroenterol Hepatol. 11:681–688.e3. 2013. View Article : Google Scholar : PubMed/NCBI
7	Hofsli E, Sjursen W, Prestvik WS, Johansen J, Rye M, Tranø G, Wasmuth HH, Hatlevoll I and Thommesen L: Identification of serum microRNA profiles in colon cancer. Br J Cancer. 108:1712–1719. 2013. View Article : Google Scholar : PubMed/NCBI
8	Luo X, Stock C, Burwinkel B and Brenner H: Identification and evaluation of plasma microRNAs for early detection of colorectal cancer. PLoS One. 8:e628802013. View Article : Google Scholar : PubMed/NCBI
9	Toiyama Y, Takahashi M, Hur K, Nagasaka T, Tanaka K, Inoue Y, Kusunoki M, Boland CR and Goel A: Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst. 105:849–859. 2013. View Article : Google Scholar : PubMed/NCBI
10	Wang S, Xiang J, Li Z, Lu S, Hu J, Gao X, Yu L, Wang L, Wang J, Wu Y, et al: A plasma microRNA panel for early detection of colorectal cancer. Int J Cancer. 136:152–161. 2015. View Article : Google Scholar : PubMed/NCBI
11	Aslam MI, Taylor K, Pringle JH and Jameson JS: microRNAs are novel biomarkers of colorectal cancer. Br J Surg. 96:702–710. 2009. View Article : Google Scholar : PubMed/NCBI
12	Chen CZ, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar : PubMed/NCBI
13	Croce CM and Calin GA: miRNAs, cancer, and stem cell ivision. Cell. 122:6–7. 2005. View Article : Google Scholar : PubMed/NCBI
14	Stiegelbauer V, Perakis S, Deutsch A, Ling H, Gerger A and Pichler M: MicroRNAs as novel predictive biomarkers and therapeutic targets in colorectal cancer. World J Gastroenterol. 20:11727–11735. 2014. View Article : Google Scholar : PubMed/NCBI
15	Zhang J, Zhang K, Bi M, Jiao X, Zhang D and Dong Q: Circulating microRNA expressions in colorectal cancer as predictors of response to chemotherapy. Anticancer Drugs. 25:346–352. 2014. View Article : Google Scholar : PubMed/NCBI
16	Molina-Pinelo S, Carnero A, Rivera F, Estevez-Garcia P, Bozada JM, Limon ML, Benavent M, Gomez J, Pastor MD, Chaves M, et al: MiR-107 and miR-99a-3p predict chemotherapy response in patients with advanced colorectal cancer. BMC Cancer Sep. 14:6562014. View Article : Google Scholar
17	Ge Q, Zhou Y, Lu J, Bai Y, Xie X and Lu Z: miRNA in plasma exosome is stable under different storage conditions. Molecules. 19:1567–1575. 2014. View Article : Google Scholar
18	Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ and Lötvall JO: Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 9:654–659. 2007. View Article : Google Scholar : PubMed/NCBI
19	Simons M and Raposo G: Exosomes-vesicular carriers for intercelluar communication. Curr Opin Cell Biol. 21:575–581. 2009. View Article : Google Scholar : PubMed/NCBI
20	Hannafon BN and Ding WQ: Intercelluar communication by exosome-derived microRNAs in cancer. Int J Mol Sci. 14:14240–14269. 2013. View Article : Google Scholar : PubMed/NCBI
21	Zhu M, Huang Z, Zhu D, Zhou X, Shan X, Qi LW, Wu L, Cheng W, Zhu J, Zhang L, et al: A panel of microRNA signature in serum for colorectal cancer diagnosis. Oncotarget. 8:17081–17091. 2017.PubMed/NCBI
22	Zhou X, Wen W, Shan X, Zhu W, Xu J, Guo RH, Cheng WF, Wang F, Qi LW, Chen Y, et al: A six-microRNA panel in plasma was identified as a potential biomarker for lung adenocarcinoma diagnosis. Oncotarget. 8:6513–6525. 2017.PubMed/NCBI
23	Liu Q, Yu Z, Yuan S, Xie W, Li C, Hu Z, Xiang Y, Wu N, Wu L, Bai L and Li Y: Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget. 8:13048–13058. 2017.PubMed/NCBI
24	Tsukamoto M, Iinuma H, Yagi T, Matsuda K and Hashiguchi Y: Circulating exosomal MicroRNA-21 as a biomarker in each tumor stage of colorectal cancer. Oncology. 92:360–370. 2017. View Article : Google Scholar : PubMed/NCBI
25	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
26	Takano Y, Masuda T, Iinuma H, Yamaguchi R, Sato K, Tobo T, Hirata H, Kuroda Y, Nambara S, Hayashi N, et al: Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer. Oncotarget. 8:78598–78613. 2017. View Article : Google Scholar : PubMed/NCBI
27	Banzhaf-Strathmann J and Edbauer D: Good guy or bad guy: The opposing roles of microRNA 125b in cancer. Cell Commun Signal. 12:302014. View Article : Google Scholar : PubMed/NCBI
28	Yamada A, Horimatsu T, Okugawa Y, Nishida N, Honjo H, Ida H, Kou T, Kusaka T, Sasaki Y, Yagi M, et al: Serum miR-21, miR-29a, and miR-125b are promising biomarkers for the early detection of colorectal neoplasia. Clin Cancer Res. 21:4234–4242. 2015. View Article : Google Scholar : PubMed/NCBI
29	Svoboda M, Izakovicova Holla L, Sefr R, Vrtkova I, Kocakova I, Tichy B and Dvorak J: Micro-RNAs miR125b and miR137 are frequently upregulated in response to capecitabine chemoradiotherapy of rectal cancer. Int J Oncol. 33:541–547. 2008.PubMed/NCBI
30	D'Angelo E, Fassan M, Maretto I, Pucciarelli S, Zanon C, Digito M, Rugge M, Nitti D and Agostini M: Serum miR-125b is a non-invasive predictive biomarker of the pre-operative chemoradiotherapy responsiveness in patients with rectal adenocarcinoma. Oncotarget. 7:28647–28657. 2016.PubMed/NCBI
31	Tanaka H, Hazama S, Iida M, Tsunedomi R, Takenouchi H, Nakajima M, Tokumitsu Y, Kanekiyo S, Shindo Y, Tomochika S, et al: miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. Cancer Sci. 108:2229–2238. 2017. View Article : Google Scholar : PubMed/NCBI
32	Hansen TF, Carlsen AL, Heegaard NH, Sørensen FB and Jakobsen A: Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer. Br J Cancer. 112:624–629. 2015. View Article : Google Scholar : PubMed/NCBI
33	Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, et al: lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling. Nat Med. 23:1331–1341. 2017. View Article : Google Scholar : PubMed/NCBI