MikroRNA-106a’nın Yüksek Ekspresyonu Kolorektal Kanserlerde Mikrosatellit İnstablite Durumu ile İlişkilidir

Yıl 2021, , 225 - 231, 01.08.2021

Seçil Ak Aksoy , Berrin Tunca , Tuncay Yılmazlar Ersin Öztürk Fuat Aksoy , Özgen Işık , Ömer Yerci , Nesrin Uğraş , Özkan Kanat , Melis Mutlu Çağla Tekin

https://doi.org/10.32708/uutfd.917784

Öz

Mikrosatellit instabilite (MSI), DNA tamir genlerindeki hatalardan kaynaklanan ve kolorektal kanserin (KRK) oluşmasına neden olan genetik bir durumdur. Sporadik KRK’larda MSI görülme sıklığı, prognoza olan etkisi literatürde çelişkilidir. Bununla birlikte MSI’ya sahip KRK’larda standart kemoterapi yetersiz kaldığı için yeni tedavi seçeneklerine ihtiyaç duyulmaktadır. micoRNA’lar (miRNA) kanserleşme sürecinde görev alan ve tanıda, prognozda ve tedavide belirteç olarak kullanılan küçük RNA molekülleridir. Mevcut çalışmada, Türk popülasyonuna ait sporadik gelişen KRK’larda MSI’nın görülme sıklığının tanımlanması ve bu tümörlerde miRNA’ların ekspresyon farklılıklarının belirlenmesi amaçlanmıştır. Çalışmada, sporadik KRK tanısı almış 63 hasta değerlendirildi. Hastalara ait arşiv tümör ve normal dokula-rından DNA ve RNA izolasyonları yapıldı. DNA örneklerinden fragment analizine dayalı MSI testi gerçekleştirildi. qRT-PCR kullanılarak 38 farklı miRNA’nın ekspresyon profili incelendi. 63 hastada MSI görülme oranı %23.8 olarak belirlendi. MSI ve mikrosatellit stabil (MSS) tümörler karşılaştırıldığında, MSI tümörlerde, miR-124 ve miR-106a’nın yüksek ve miR-145’in ise düşük ekspresyon gösterdiği belirlendi (p<0.05). Bununla birlikte miR-106a’nın yüksek ekspresyonunun cerrahi sonrası nüks gelişimi ile ilişkili olduğu saptandı (p=0.002). Elde edilen bulgular ışığında miR-106a’nın özellikle MSI genotipine sahip KRK tümörlerde hedeflenmesi ile KRK hastalarında yeni tedavi protokollerinin oluşturularak nüks oluşumunun engellenebileceğini öngörülmüştür.

Anahtar Kelimeler

Sporadik Kolorektal Kanser, Mikrosatellit İnstability, MikroRNA, miR-106a

Destekleyen Kurum

Bursa Uludağ Üniversitesi

Proje Numarası

KUAP(T)2014/35

Upregulation of Microrna-106a is Associated with Microsatellite Instability Status in Colorectal Cancer

Öz

Microsatellite instability (MSI) is a genetic condition that results from errors in DNA repair genes and causes colorectal cancer (CRC). The incidence of MSI in sporadic CRCs and its effect on prognosis are contradictory in the literature. However, since standard chemotherapy is insufficient in CRCs with MSI, new treatment options are needed. micoRNAs (miRNAs) are small RNA molecules that take part in the cancer process and are used as markers in diagnosis, prognosis and treatment. In the study, it is aimed to define the prevalence of MSI in sporadically developing CRCs belonging to the Turkish population and to determine the expression differences of miRNAs in these tumors. 63 patients diagnosed with sporadic CRC were evaluated in the study. DNA and RNA isolations were made from archive tumor and normal tissues of the patients. MSI test was performed based on fragment analysis from DNA samples. The expression profiles of 38 different miRNAs were examined using qRT-PCR. In 63 patients, the incidence of MSI was determined as 23.8%. When MSI and microsatellite stable (MSS) tumors were compared, it was determined that miR-124 and miR-106a showed high expression and miR-145 low expression in MSI tumors (p <0.05). However, high expression of miR-106a was found to be associated with postoperative recurrence (p=0.002). In the light of the findings obtained, we think that by targeting miR-106a especially in CRC tumors with MSI genetype, recurrence can be prevented by creating new treatment protocols in these tumors.

Anahtar Kelimeler

Sporadic colorektal cancer, Mikrosatellite Instability, MicroRNA, miR-106a

Proje Numarası

KUAP(T)2014/35

Kaynakça

• Siegel R., Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, Jemal A (2017) Colorectal cancer statistics, CA A Cancer J Clin. 67; 177–193.
• Siegel, R. L.,Miller, K. D. & Jemal, A. Cancer Statistics, (2017).CA Cancer J. Clin. 67,7–30.
• Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N. Colorectal cancer. Lancet 2010; 375: 1030–1047.
• Marisa L, de Reynies A, Duval A, et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med 2013;10:e1001453.
• Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990;61:759-767.
• Becht E, de Reynies A, Giraldo NA, et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypesand relevant for precision immunotherapy. Clin Cancer Res. 2016;22:4057-4066.
• De la Chapelle A (2003) Microsatellite instability. The New England journal of medicine 349: 209–210.
• Baudrin LG, Deleuze JF, How-Kit A. Molecular and computational methods for the detection of microsatellite instability in cancer. Front. Oncol. 2018;8:621.
• Carr PR, Alwers E, Bienert S, Weberpals J, Kloor M, Brenner H, Hoffmeister M. Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses. Ann. Oncol. 2018:4:825–834.
• Lu Y, Soong TD, Elemento O. A novel approach for characterizing microsatellite instability in cancer cells. PLoS One 2013;8(5):e63056.
• Zaanan A, Taieb J. Predictive and prognostic value of MSI phenotype in adjuvant colon cancer: Who and how to treat? Bull Cancer. 2019;106(2):129-136.
• Huang Z, Chen X, Liu C, Cui L. The Clinical Significance of Microsatellite Instability in Precision Treatment. Methods Mol Biol. 2020;2204:33-38.
• Saridaki Z, Souglakos J, Georgoulias V. Prognostic and predictive significance of MSI in stages II/III colon cancer. World J Gastroenterol. 2014 Jun 14;20(22):6809-14.
• Sakimoto T, Chika N, Suzuki O, Ishibashi K, Tachikawa T, Akagi K, Eguchi H, Okazaki Y, Ishida H. Evaluation of BRAF V600E Mutations in High-Level Microsatellite Instability(MSI-H)Colon Cancer - Comparison Between Genetic Testing and Immunohistochemical Staining. Gan To Kagaku Ryoho. 2016 Nov;43(12):1693-1695.
• Siskova A, Cervena K, Kral J, Hucl T, Vodicka P, Vymetalkova. Colorectal Adenomas-Genetics and Searching for New Molecular Screening Biomarkers. Int J Mol Sci. 2020 May 5;21(9):3260.
• Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv. Exp. Med. Biol. 2013;774:1–20.
• Hussen BM, Hidayat HJ, Salihi A, Sabir DK, Taheri M, Ghafouri-Fard S. MicroRNA: A signature for cancer progression. Biomed Pharmacother. 2021 Mar 23;138:111528.
• Pan G, Liu Y, Shang L, Zhou F, Yang S. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond). 2021 Mar;41(3):199-217.
• Ak S, Tunca B, Tezcan G, Cecener G, Egeli U, Yilmazlar T, Ozturk E, Yerci O. MicroRNA expression patterns of tumors in early-onset colorectal cancer patients. J Surg Res. 2014 Sep;191(1):113-22.
• Brînzan C, Aşchie M, Cozaru G, Dumitru E, Mitroi A. The diagnostic value of miR-92a, -143, and -145 expression levels in patients with colorectal adenocarcinoma from Romania. Medicine (Baltimore). 2020 Aug 28;99(35):e21895.
• Bai JW, Xue HZ, Zhang C. Down-regulation of microRNA-143 is associated with colorectal cancer progression. Eur Rev Med Pharmacol Sci 2016; 20 (22): 4682-4687.
• Jay C, Nemunaitis J, Chen P, et al. miRNA profiling for diagnosis and prognosis of human cancer. DNA Cell Biol. 2007; 26: 293–300.
• Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008; 18: 997–1006.
• Liu J Chen Z, Xiang J, and Gu X. DNA methylation mediated silencing of microRNA-145 is a potential prognostic marker in patients with lung adenocarcinoma. Sci Rep. 2015;5:16901.
• Orosz E, Kiss I, Gyöngyi Z, Varjas T. Expression of Circulating miR-155, miR-21, miR-221, miR-30a, miR-34a and miR-29a: Comparison of Colonic and Rectal Cancer. In Vivo. 2018 Nov-Dec;32(6):1333-1337.
• Yamamoto H, Adachi Y, Taniguchi H, Kunimoto H, Nosho K, Suzuki H, Shinomura Y. Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol. 2012 Jun 14;18(22):2745-55.
• Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM. Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6982-7.
• Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol. 2015 Jun;89(6):899-921.
• Qin Z, Liu X. miR-124, a potential therapeutic target in colorectal cancer. Onco Targets Ther. 2019 Jan 22;12:749-751.
• Silber J, Hashizume R, Felix T, Hariono S, Yu M, Berger MS, Huse JT, VandenBerg SR, James CD, Hodgson JG, Gupta N. Expression of miR-124 inhibits growth of medulloblastoma cells. Neuro Oncol. 2013 Jan;15(1):83-90.
• Ruan F, Wang YF, Chai Y. Diagnostic Values of miR-21, miR-124, and M-CSF in Patients With Early Cervical Cancer. Technol Cancer Res Treat.
• Silva CMS, Barros-Filho MC, Wong DVT, Mello JBH, Nobre LMS, et al. Circulating let-7e-5p, miR-106a-5p, miR-28-3p, and miR-542-5p as a Promising microRNA Signature for the Detection of Colorectal Cancer. Cancers (Basel). 2021 Mar 24;13(7):1493.
• Liu Z, Qin Y, Dong S, Chen X, Huo Z, Zhen Z. Overexpression of miR-106a enhances oxaliplatin sensitivity of colorectalcancer through regulation of FOXQ1.