A systematic approach introduced novel targets in rectal cancer by considering miRNA/mRNA interactions in response to radiotherapy

Article type: Research Article

Authors: Khalighfard, Solmaz^{a; b} | Kalhori, Mohammad Reza^c | Amiriani, Taghi^d | Poorkhani, Amirhoushang^d | Khori, Vahid^d | Esmati, Ebrahim^a | Lashkari, Marzieh^a | Najafi, Ali^{e; 1} | Alizadeh, Ali Mohammad^{b; f; 1; *}

Affiliations: [a] Radiation Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran | [b] Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran | [c] Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran | [d] Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran | [e] Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran | [f] Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran

Correspondence: [*] Corresponding author: Ali Mohammad Alizadeh, Cancer Research Center, Tehran University of Medical Sciences, Tehran, P.O. 1419733141, Iran. Tel./Fax: +98 21 6119 2501; E-mail: aalizadeh@sina.tums.ac.ir.

Note: [1] Ali Najafi and Ali Mohammad Alizadeh contributed equally to this work.

Abstract: BACKGROUND: The discovery of miRNA/mRNA interactions in several biological samples prompted the researchers to explore new biomarkers in tumors. OBJECTIVE: We aimed to investigate the interactions of miRNA/mRNA in response to radiotherapy in the plasma samples of rectal cancer patients. METHODS: Five microarray datasets related to cancerous and non-cancerous individuals were first used to construct networks. The databases of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyze pathway enrichment. The plasma samples were then collected from 55 patients with recently diagnosed rectal cancer and 10 healthy subjects. For radiotherapy courses, the patients have consecutively received 30 sessions of local radiation for six weeks. At last, the expression of selected genes and miRNAs was experimentally measured before and after radiotherapy by qPCR, and the protein levels of the target genes were measured by ELISA assay. We evaluated the therapeutic responses based on the tumor regression grade of the Dworak classification. RESULTS: We identified 5 up-regulated and 5 down-regulated miRNAs and 8 up-regulated and 3 down-regulated genes of the databases. There was a significant increase in tumor suppressor miRNAs, including miR-101-3p, miR-145-5p, miR-26a-5p, miR-34a-5p, and a significant decrease in oncomiRs, including miR-221-3p and miR-17-5p, after radiotherapy compared to the pre-treatment. Moreover, the up-regulated miR-17-5p and miR-221-5p and the down-regulated miR-101-3p and miR-145-5p were directly related to rectal cancer through the interaction with the Wnt, RAS, PI3K, and TGF-β signaling pathways. An analysis of receiver operating characteristics showed that miRNAs 221, 17, and 23 were response-related in locally advanced rectal cancer patients. CONCLUSIONS: It seems that monitoring the miRNA/mRNA interactions during radiotherapy can be an appropriate diagnostic tool to track the recovery process and respond to standard therapies.

Keywords: Radiotherapy, rectal cancer, gene, protein, microarray, microRNA

DOI: 10.3233/CBM-210079

Journal: Cancer Biomarkers, vol. 33, no. 1, pp. 97-110, 2022