Expression dynamics of hsa-miR-18a-5p and hsa-miR-135b-5p are associated with pathological tumor stage and lymph node status in locally advanced rectal cancer patients undergoing neoadjuvant chemoradiotherapy
DOI:
https://doi.org/10.2298/ABS251021033RKeywords:
hsa-miR-18a-5p, hsa-miR-135b-5p, neoadjuvant chemoradiotherapy, locally advanced rectal cancerAbstract
Paper description:
- The expression of hsa-miR-18a-5p decreases significantly after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC).
- High hsa-miR-18a-5p levels before treatment is associated with disease downstaging.
- The expression of hsa-miR-135b-5p after nCRT was associated with advanced tumor stage and lymph node involvement.
- Neither miRNA showed a significant association with response to therapy. Both reflect tumor biology and may assist in patient stratification.
Abstract: Locally advanced rectal cancer (LARC) is characterized by tumor invasion into surrounding tissues and frequent lymph node involvement, often requiring neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection. LARC presents a significant therapeutic challenge because it is typically diagnosed at an advanced stage and shows variable responses to standard nCRT, highlighting the need for predictive biomarkers. microRNAs are considered valuable biomarker candidates due to their biological characteristics. We investigated the expression dynamics of hsa-miR-18a-5p and hsa-miR-135b-5p and their predictive potential for response to nCRT. We demonstrate a significant post-nCRT decrease in tumor expression of hsa-miR-18a-5p. High pre-treatment hsa-miR-18a-5p expression was significantly associated with lower post-treatment pathological stage and absence of lymph node metastasis, indicating potential predictive value. The expression of hsa-miR-135b-5p after therapy was associated with advanced disease stage and positive lymph node status, indicating it may be linked to more aggressive disease after the treatment. Despite these associations with tumor characteristics, neither miRNA showed a significant association with therapy response. Our findings suggest that while hsa-miR-18a-5p and hsa-miR-135b-5p are not predictive of nCRT response, their expression patterns before and after therapy may reflect underlying tumor biology and hold potential for LARC patient stratification.
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Sung H, Ferlay J, Siegel RL. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-49. http://doi.org/10.3322/caac.21660
Bray F, Laversanne M, Sung H. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63. http://doi.org/10.3322/caac.21834
Morgan E, Arnold M. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72:338-44. http://doi.org/10.1136/gutjnl-2022-327736
Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138:2059-72. http://doi.org/10.1053/j.gastro.2009.12.06
Pettit C, Walston S, Wald P, Webb A, Williams TM. Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review). Int J Oncol. 2017;51:393-404. http://doi.org/10.3892/ijo.2017.4045
Imedio L, Cristóbal I, Rubio J, Santos A, Rojo F, García-Foncillas J. MicroRNAs in Rectal cancer: functional significance and promising therapeutic value. Cancers. 2020;12:2040. http://doi.org/10.3390/cancers12082040
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522-31. http://doi.org/10.1038/nrg1379
Hill M, Tran N. miRNA interplay: mechanisms and consequences in cancer. Dis Model Mech. 2021;14:dmm047662. http://doi.org/10.1242/dmm.047662
Ardekani AM, Naeini MM. The role of microRNAs in human diseases. Avicenna J Med Biotechnol. 2010;2:161-79.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203-22. http://doi.org/10.1038/nrd.2016.246
De Palma FDE, Luglio G, Tropeano FP. The role of microRNAs and circulating tumor markers as predictors of response to neoadjuvant therapy in locally advanced rectal cancer. Int J Mol Sci. 2020;21:7040. http://doi.org/10.3390/ijms21197040
Fasano M, Pirozzi M, Miceli CC, Cocule M, Caraglia M. TGF-β modulated pathways in colorectal cancer: new potential therapeutic opportunities. Int J Mol Sci. 2024;25:7400. http://doi.org/10.3390/ijms25137400
Rosic J, Dragicevic S, Miladinov M, Despotovic J, Bogdanovic A, Krivokapic Z, Nikolic A. SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response. Exp Mol Pathol. 2021;123:104714. http://doi.org/10.1016/j.yexmp.2021.104714
Despotovic J, Dragicevic S, Nikolic A. Effects of chemotherapy for metastatic colorectal cancer on the TGF-β signaling and related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p. Cell Biochem Biophys. 2021;79:757-67. http://doi.org/10.1007/s12013-021-00980-3
Li X, Zhang G, Luo F, Ruan J, Huang D, Feng D, Xiao D, Zeng Z, Chen X, Wu W. Identification of aberrantly expressed miRNAs in rectal cancer. Oncol Rep. 2012;28:77-84. http://doi.org/10.3892/or.2012.1769
Shen K, Cao Z, Zhu R, You L, Zhang T. The dual functional role of microRNA-18a (miR-18a) in cancer development. Clin Transl Med. 2019;8:32. http://doi.org/10.1186/s40169-019-0250-9
Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009;4:199-227. http://doi.org/10.1146/annurev.pathol.4.110807.092222
Gaedcke J, Grade M, Camps J, Søkilde R, Kaczkowski B, Schetter AJ, Difilippantonio MJ, Harris CC, Ghadimi BM, Møller S, Beissbarth T, Ried T, Litman T. The rectal cancer microRNAome-microRNA expression in rectal cancer and matched normal mucosa. Clin Cancer Res. 2012;18:4919-30. http://doi.org/10.1158/1078-0432.ccr-12-0016
Chang L, Zhou G, Soufan O, Xia J. miRNet 2.0: network-based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. 2020;48:W244-w51. http://doi.org/10.1093/nar/gkaa467
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G, Ollivier JM, Bonvalot S, Gignoux M. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680-6. http://doi.org/10.1002/1097-0142(19940601)73:11<2680::aid-cncr2820731105>3.0.co;2-c
Millino C, Maretto I, Pacchioni B, Digito M, De Paoli A, Canzonieri V, D'Angelo E, Agostini M, Rizzolio F, Giordano A, Barina A, Rajendran S, Esposito G, Lanfranchi G, Nitti D, Pucciarelli S. Gene and microRNA expression are predictive of tumor response in rectal adenocarcinoma patients treated with preoperative chemoradiotherapy. J Cell Physiol. 2017;232:426-35. https://doi.org/10.1002/jcp.25441
Della Vittoria Scarpati G, Falcetta F, Carlomagno C, Ubezio P, Marchini S, De Stefano A, Singh VK, D'Incalci M, De Placido S, Pepe S. A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012;83:1113-9. http://doi.org/10.1016/j.ijrobp.2011.09.030
Conde-Muiño R, Cano C, Sánchez-Martín V, Herrera A, Comino A, Medina PP, Palma P, Cuadros M. Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc. Oncotarget. 2017;8:82294-302. http://doi.org/10.18632/oncotarget.19393
Nikolic A, Krivokapic Z. Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Surg Oncol. 2022;41:101743. http://doi.org/10.1016/j.suronc.2022.101743
Quah HM, Chou JF, Gonen M, Shia J, Schrag D, Saltz LB, Goodman KA, Minsky BD, Wong WD, Weiser MR. Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer 2008;113:57-64. http://doi.org/10.1002/cncr.23516
Wen B, Zhang L, Wang C, Huang R, Peng H, Zhang T, Dong J, Xiao W, Zeng Z, Liu M, Gao Y. Prognostic significance of clinical and pathological stages on locally advanced rectal carcinoma after neoadjuvant chemoradiotherapy. Radiat Oncol. 2015;10:124. http://doi.org/10.1186/s13014-015-0425-5
Stojkovic G, Jovanovic I, Dimitrijevic M, Jovanovic J, Tomanovic N, Stankovic A, Arsovic N, Boricic I, Zeljic K. Meta-signature guided investigation of miRNA candidates as potential biomarkers of oral cancer. Oral Dis. 2023;29:1550-64. http://doi.org/10.1111/odi.14185
Ourô S, Mourato C, Velho S, Cardador A, Ferreira MP, Albergaria D, Castro RE, Maio R, Rodrigues CMP. Potential of miR-21 to predict incomplete response to chemoradiotherapy in rectal adenocarcinoma. Front Oncol. 2020;10:577653. http://doi.org/10.3389/fonc.2020.577653
Badr D, Fouad MA, Hussein M, Salem S, Zekri A, Shouman S. Rebound increase in microRNA levels at the end of 5-FU-based therapy in colorectal cancer patients. Sci Rep. 2023;13:14237. http://doi.org/10.1038/s41598-023-41030-7
Chen X, Wu L, Li D, Xu Y, Zhang L, Niu K, Kong R, Gu J, Xu Z, Chen Z, Sun J. Radiosensitizing effects of miR-18a-5p on lung cancer stem-like cells via downregulating both ATM and HIF-1α. Cancer Med. 2018;7:3834-47. http://doi.org/10.1002/cam4.1527
Liu B, Liu Y, Zhao L, Pan Y, Shan Y, Li Y, Jia L. Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway. Mol Carcinog. 2017;56:2669-80. http://doi.org/10.1002/mc.22710
Machackova T, Prochazka V, Kala Z, Slaby O. Translational potential of micrornas for preoperative staging and prediction of chemoradiotherapy response in rectal cancer. Cancers (Basel). 2019;11:1545. http://doi.org/10.3390/cancers11101545
Caramés C, Cristóbal I, Moreno V, del Puerto L, Moreno I, Rodriguez M, Marín JP, Correa AV, Hernández R, Zenzola V, Hernández T, León A, Martín JI, Sánchez-Fayos P, García-Olmo D, Rojo F, Goel A, Fernandez-Aceñero MJ, García-Foncillas J. MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int J Colorectal Dis. 2015;30:899-906. http://doi.org/10.1007/s00384-015-2231-9
Svoboda M, Sana J, Fabian P, Kocakova I, Gombosova J, Nekvindova J, Radova L, Vyzula R, Slaby O. MicroRNA expression profile associated with response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. Radiat Oncol. 2012;7:195. http://doi.org/10.1186/1748-717x-7-195
Wada Y, Shimada M, Morine Y. Circulating miRNA signature predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. JCO Precis Oncol. 2021;5:PO.21.00015. http://doi.org/10.1200/po.21.00015
Cristóbal I, Rubio J, Santos A, Torrejón B, Caramés C. MicroRNA-199b downregulation confers resistance to 5-fluorouracil treatment and predicts poor outcome and response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. Cancers. 2020;12:1655. http://doi.org/10.3390/cancers12061655
Lim SH, Chua W, Henderson C, Ng W, Shin JS, Chantrill L, Asghari R, Lee CS, Spring KJ, de Souza P. Predictive and prognostic biomarkers for neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Crit Rev Oncol Hematol. 2015;96:67-80. http://doi.org/10.1016/j.critrevonc.2015.05.003
Losurdo P, Gandin I, Belgrano M, Fiorese I, Verardo R, Zanconati F, Cova MA, de Manzini N. microRNAs combined to radiomic features as a predictor of complete clinical response after neoadjuvant radio-chemotherapy for locally advanced rectal cancer: a preliminary study. Surg Endosc. 2023;37:3676-83. http://doi.org/10.1007/s00464-022-09851-1
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Copyright (c) 2025 Ksenija Rankovic, dr Jovana Despotovic, dr Jovana Rosic Stojkovic, dr Katarina Eric, dr Marko Miladinov, prof. dr Goran Barisic, prof. dr Katarina Zeljic
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