Association between the expression level of miRNA‑374a and TGF‑&beta;1 in patients with colorectal cancer

Bader El Din,Noha G.; El‑Shenawy,Reem; Moustafa,Rehab I.; Khairy,Ahmed; Farouk,Sally

doi:10.3892/wasj.2024.283

Association between the expression level of miRNA‑374a and TGF‑β1 in patients with colorectal cancer

Authors:
- Noha G. Bader El Din
- Reem El‑Shenawy
- Rehab I. Moustafa
- Ahmed Khairy
- Sally Farouk
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Affiliations: Microbial Biotechnology Department, National Research Centre, Dokki 12622, Egypt, Endemic Medicine Department, Faculty of Medicine, Cairo University, Giza 11559, Egypt
Published online on: October 7, 2024 https://doi.org/10.3892/wasj.2024.283
Article Number: 68
Copyright : © Bader El Din et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Colorectal cancer (CRC) poses a significant threat to global health with increasing incidence and mortality rates. Exploring different molecular mechanisms and aspects underlying the development and progression of CRC will promote the early diagnosis and lead to better outcomes. MicroRNAs (miRNAs/miRs) are one of the molecular aspects related to the development and diagnosis of CRC. The present study aimed to investigate the association between the expression levels of miRNA‑374a and transforming growth factor (TGF)‑β1 in patients with CRC to explore the roles of these markers in carcinogenesis and their use as diagnostic biomarkers. For this purpose, 195 subjects were enrolled. The expression level of miRNA‑374a was assessed in serum samples of 145 subjects (screening phase) in addition to 50 CRC tissue samples to validate the tumor‑derived expression of miRNA‑374a (confirmation phase). The analysis of miRNA‑374a expression was performed by the extraction of miRNAs followed by reverse transcription‑quantitative PCR. Additionally, the TGF‑β1 level was measured in all patients with CRC and control serum samples. ROC curve analysis was performed to determine the diagnostic potential of miRNA‑374a and TGF‑β1. The patients with CRC exhibited significantly elevated levels of miRNA‑374a compared with the healthy individuals, with a fold change of 12.92 (P=0.0001). Moreover, the expression of miRNA‑374a varied, depending on the CRC grade; patients with grade I disease exhibited a 9.2‑fold increase and those with grade II disease a 21.84‑fold increase in miRNA‑374a expression. The relative expression level of miRNA‑374a in CRC tissues was significantly upregulated by 4.48‑fold compared with the adjacent non‑cancerous tissues (P<0.001). Furthermore, the TGF‑β1 expression level was significantly elevated in patients with CRC compared with the controls (P=0.0001). The area under the curve was 0.9560 for CRC serum samples (P<0.0001), 0.8972 for CRC tissue (P<0.0001) and 0.8075 for TGF‑β1 expression levels (P=0.001). In addition, a positive correlation was found between the miRNA‑374 expression level and TGF‑β1 serum levels (Rho=0.8912, P=<0.0001). On the whole, the present study demonstrates that the elevated expression levels of miRNA‑374 and TGF‑β1 in patients with CRC indicate their crucial roles in driving tumor progression and highlight their potential for use diagnostic biomarkers and therapeutic targets in CRC.

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1	Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A and Bray F: Cancer statistics for the year 2020: An overview. Int J Cancer: April 5, 2021 (Epub ahead of print).
2	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017.PubMed/NCBI View Article : Google Scholar
3	Marx O, Mankarious M and Yochum G: Molecular genetics of early-onset colorectal cancer. World J Biol Chem. 14:13–27. 2023.PubMed/NCBI View Article : Google Scholar
4	Allam AR, Elsayed MA, Daghash IT, Abdelaziz AM, Mostafa OM, Sabra HK, Eldaboush AM, Ahmed NMB, Elweza RT, Adwy ES, et al: Colonoscopy screening for colorectal cancer in Egypt: A nationwide cross-sectional study. BMC Cancer. 24(131)2024.PubMed/NCBI View Article : Google Scholar
5	Rashad N, Salem SE, Meheissen MAM, Refaat G, Sami HM, Temerik A, Kordy N, Daniel MA, El-Kaffas M, Esam M, et al: Early-onset colorectal cancer in Egypt: Pathological characters, patterns of care, and survival compared to average-age onset colorectal cancer: A retrospective multicenter study. JCO Glob Oncol. 10(e2300372)2024.PubMed/NCBI View Article : Google Scholar
6	Ibrahim AH and Shash E: General oncology care in Egypt. In: Al-Shamsi HO, Abu-Gheida IH, Iqbal F and Al-Awadhi A (eds). Cancer in the Arab World. Singapore: Springer Singapore, pp41-61, 2022.
7	Aran V, Victorino AP, Thuler LC and Ferreira CG: Colorectal cancer: Epidemiology, disease mechanisms and interventions to reduce onset and mortality. Clin Colorectal Cancer. 15:195–203. 2016.PubMed/NCBI View Article : Google Scholar
8	Farouk S, El-Shenawy R, Khairy AM and Bader El-Din NG: Overexpression of miRNA 26a and 26b with MMP-9 are valuable diagnostic biomarkers for colorectal cancer patients. Biomark Med. 17:159–169. 2023.PubMed/NCBI View Article : Google Scholar
9	Ahmadi A, Bayatiani MR, Seif F, Ansari J, Rashidi P, Moghadasi M and Etemadi M: Evaluation of zadiotherapy on miR-374 gene expression in colorectal cancer patient blood samples. Rep Biochem Mol Biol. 10:614–621. 2022.PubMed/NCBI View Article : Google Scholar
10	Ahmad R, Singh JK, Wunnava A, Al-Obeed O, Abdulla M and Srivastava SK: Emerging trends in colorectal cancer: Dysregulated signaling pathways (review). Int J Mol Med. 47(14)2021.PubMed/NCBI View Article : Google Scholar
11	Pasquier J, Abu-Kaoud N, Al Thani H and Rafii A: Epithelial to mesenchymal transition in a clinical perspective. J Oncol. 2015(792182)2015.PubMed/NCBI View Article : Google Scholar
12	Lei Y, Chen L, Zhang G, Shan A, Ye C, Liang B, Sun J, Liao X, Zhu C, Chen Y, et al: MicroRNAs target the Wnt/β-catenin signaling pathway to regulate epithelial-mesenchymal transition in cancer (review). Oncol Rep. 44:1299–1313. 2020.PubMed/NCBI View Article : Google Scholar
13	Smolarz B, Durczyński A, Romanowicz H, Szyłło K and Hogendorf P: miRNAs in cancer (review of literature). Int J Mol Sci. 23(2805)2022.PubMed/NCBI View Article : Google Scholar
14	Di Z, Di M, Fu W, Tang Q, Liu Y, Lei P, Gu X, Liu T and Sun M: Integrated analysis identifies a nine-microRNA signature biomarker for diagnosis and prognosis in colorectal cancer. Front Genet. 11(192)2020.PubMed/NCBI View Article : Google Scholar
15	Kim Y, Sim J, Kim H, Bang SS, Jee S, Park S and Jang K: MicroRNA-374a expression as a prognostic biomarker in lung adenocarcinoma. J Pathol Transl Med. 53:354–360. 2019.PubMed/NCBI View Article : Google Scholar
16	Choi JA, Kim H, Kwon H, Lee EH, Cho H, Chung JY and Kim JH: Ascitic autotaxin as a potential prognostic, diagnostic, and therapeutic target for epithelial ovarian cancer. Br J Cancer. 129:1184–1194. 2023.PubMed/NCBI View Article : Google Scholar
17	Ji R, Zhang X, Gu H, Ma J, Wen X, Zhou J, Qian H, Xu W, Qian J and Lin J: miR-374a-5p: A new target for diagnosis and drug resistance therapy in gastric cancer. Mol Ther Nucleic Acids. 18:320–331. 2019.PubMed/NCBI View Article : Google Scholar
18	O'Brien SJ, Netz U, Hallion J, Bishop C, Stephen V, Burton J, Paas M, Feagins K, Pan J, Rai SN and Galandiuk S: Circulating plasma microRNAs in colorectal neoplasia: A pilot study in assessing response to therapy. Transl Oncol. 14(100962)2021.PubMed/NCBI View Article : Google Scholar
19	Bayatiani MR, Ahmadi A, Aghabozorgi R and Seif F: Concomitant Up-regulation of Hsa-Mir-374 and down-regulation of its targets, GSK-3β and APC, in tissue samples of colorectal cancer. Rep Biochem Mol Biol. 9:408–416. 2021.PubMed/NCBI View Article : Google Scholar
20	Chen B, Xia Z, Deng YN, Yang Y, Zhang P, Zhu H, Xu N and Liang S: Emerging microRNA biomarkers for colorectal cancer diagnosis and prognosis. Open Biol. 9(180212)2019.PubMed/NCBI View Article : Google Scholar
21	Cai J, Guan H, Fang L, Yang Y, Zhu X, Yuan J, Wu J and Li M: MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis. J Clin Invest. 123:566–579. 2013.PubMed/NCBI View Article : Google Scholar
22	Vallée A, Lecarpentier Y, Guillevin R and Vallée JN: Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget. 8:90579–90604. 2017.PubMed/NCBI View Article : Google Scholar
23	Xu S, Zhou Y, Biekemitoufu H, Wang H, Li C, Zhang W and Ma Y: Expression of Twist, Slug and Snail in esophageal squamous cell carcinoma and their prognostic significance. Oncol Lett. 21(184)2021.PubMed/NCBI View Article : Google Scholar
24	Xu L, Li M, Wang M, Yan D, Feng G and An G: The expression of microRNA-375 in plasma and tissue is matched in human colorectal cancer. BMC Cancer. 14(714)2014.PubMed/NCBI View Article : Google Scholar
25	Dhasarathy A, Phadke D, Mav D, Shah RR and Wade PA: The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer. PLoS One. 6(e26514)2011.PubMed/NCBI View Article : Google Scholar
26	Calon A, Espinet E, Palomo-Ponce S, Tauriello DVF, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XHF, et al: Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 22:571–584. 2012.PubMed/NCBI View Article : Google Scholar
27	Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M and Afroze D: Transforming growth factor-beta (TGF-β) signaling in cancer-A betrayal within. Front Pharmacol. 13(791272)2022.PubMed/NCBI View Article : Google Scholar
28	Wodziński D, Wosiak A, Pietrzak J, Świechowski R, Kordek R and Balcerczak E: Assessment of the TGFB1 gene expression and methylation status of the promoter region in patients with colorectal cancer. Sci Rep. 12(11488)2022.PubMed/NCBI View Article : Google Scholar
29	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.PubMed/NCBI View Article : Google Scholar
30	Bader El Din NG, Ibrahim MK, El-Shenawy R, Salum GM, Farouk S, Zayed N, Khairy A and El Awady M: MicroRNAs expression profiling in Egyptian colorectal cancer patients. IUBMB Life. 72:275–284. 2020.PubMed/NCBI View Article : Google Scholar
31	Fu J, Imani S, Wu MY and Wu RC: MicroRNA-34 family in cancers: Role, mechanism, and therapeutic potential. Cancers (Basel). 15(4723)2023.PubMed/NCBI View Article : Google Scholar
32	Bakrim S, El Hachlafi N, Khalid A, Abdalla AN, El Omari N, Aboulaghras S, Sakran AM, Goh KW, Ming LC, Razi P and Bouyahya A: Recent advances and molecular mechanisms of TGF-β signaling in colorectal cancer, with focus on bioactive compounds targeting. Biomed Pharmacother. 177(116886)2024.PubMed/NCBI View Article : Google Scholar
33	Farouk S, Khairy A, Salem AM, Soliman AF and Bader El Din NG: Differential expression of miR-21, miR-23a, and miR-27a, and their diagnostic significance in Egyptian colorectal cancer patients. Genet Test Mol Biomarkers. 24:825–834. 2020.PubMed/NCBI View Article : Google Scholar
34	Bader El Din NG, Farouk S, Abdel-Salam LO and Khairy A: The potential value of miRNA-223 as a diagnostic biomarker for Egyptian colorectal patients. Eur J Gastroenterol Hepatol. 33:25–31. 2021.PubMed/NCBI View Article : Google Scholar
35	He W, Feng L, Xia D and Han N: MiR-374a promotes the proliferation of human osteosarcoma by downregulating FOXO1 expression. Int J Clin Exp Med. 8:3482–3489. 2015.PubMed/NCBI
36	Zhang H, Wang Z, Ma R, Wu J and Feng J: MicroRNAs as biomarkers for the progression and prognosis of colon carcinoma. Int J Mol Med. 42:2080–2088. 2018.PubMed/NCBI View Article : Google Scholar
37	Son D, Kim Y, Lim S, Kang HG, Kim DH, Park JW, Cheong W, Kong HK, Han W, Park WY, et al: miR-374a-5p promotes tumor progression by targeting ARRB1 in triple negative breast cancer. Cancer Lett. 454:224–233. 2019.PubMed/NCBI View Article : Google Scholar
38	Chen Y, Jiang J, Zhao M, Luo X, Liang Z, Zhen Y, Fu Q, Deng X, Lin X, Li L, et al: microRNA-374a suppresses colon cancer progression by directly reducing CCND1 to inactivate the PI3K/AKT pathway. Oncotarget. 7:41306–41319. 2016.PubMed/NCBI View Article : Google Scholar
39	Zhen Y, Fang W, Zhao M, Luo R, Liu Y, Fu Q, Chen Y, Cheng C, Zhang Y and Liu Z: miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplat. Oncogene. 36:275–285. 2017.PubMed/NCBI View Article : Google Scholar
40	Barnard JA, Warwick GJ and Gold LI: Localization of transforming growth factor beta isoforms in the normal murine small intestine and colon. Gastroenterology. 105:67–73. 1993.PubMed/NCBI View Article : Google Scholar
41	Li X, Wu Y and Tian T: TGF-β signaling in metastatic colorectal cancer (mCRC): From underlying mechanism to potential applications in clinical development. Int J Mol Sci. 23(14436)2022.PubMed/NCBI View Article : Google Scholar
42	Itatani Y, Kawada K and Sakai Y: Transforming growth factor-β signaling pathway in colorectal cancer and its tumor microenvironment. Int J Mol Sci. 20(5822)2019.PubMed/NCBI View Article : Google Scholar
43	Hao Y, Baker D and Ten Dijke P: TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. Int J Mol Sci. 20(2767)2019.PubMed/NCBI View Article : Google Scholar
44	Chen P, Guo X, Zhang L, Zhang W, Zhou Q, Tian Z, Zheng Y, Liao Q, Wang H, Li G, et al: MiR-200c is a cMyc-activated miRNA that promotes nasopharyngeal carcinoma by downregulating PTEN. Oncotarget. 8:5206–5218. 2017.PubMed/NCBI View Article : Google Scholar
45	Liu Q, Chen G, Moore J, Guix I, Placantonakis D and Barcellos-Hoff MH: Exploiting canonical TGFβ signaling in cancer treatment. Mol Cancer Ther. 21:16–24. 2022.PubMed/NCBI View Article : Google Scholar