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Combinatorial Chemistry & High Throughput Screening


ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Mir-21-5p and Mir-455-5p as Markers for Diagnosis and Prognosis of Rectal Adenocarcinoma may Reduce Local CD4+ and CD8+ Lymphocyte Infiltration

Author(s): Heng Deng, Haiping Shi, Xiancang Yuan* and Jun Zhang*

Volume 26, Issue 12, 2023

Published on: 15 February, 2023

Page: [2149 - 2160] Pages: 12

DOI: 10.2174/1386207326666221226155948

Price: $65


Objective: This study aimed to verify miRNAs and the molecular mechanisms of diagnostic and prognostic biomarkers for rectal adenocarcinoma.

Methods: Two miRNA datasets of rectal adenocarcinoma were obtained from GEO and TCGA. GEO2R tool, Venn diagram, Kaplan-Meier survival analysis, KEGG pathway analyses, DIANA TOOLS, and Wilcoxon rank-sum test were used for biological information analysis. The diagnostic utility of miRNAs and immune infiltration of tumors in Chinese patients were validated by RTqPCR and immunofluorescence analysis.

Results: MiR-21-5P and miR-455-5p were both found to have a significant correlation with poor prognosis and higher expression in rectal adenocarcinoma. Besides, the ability to prognosis was independent of the clinicopathological stage. MiR-21-5P and miR-455-5p were enriched in the TGF-beta, Wnt, MAKP, and PI3K-AKT signaling pathways. Meanwhile, the high expression phenotype of miR-21-5P and miR-455-5p decreased CD4+ and CD8+ T cells.

Conclusion: In summary, we found two significant diagnostic and prognostic miRNAs of rectal adenocarcinoma via integrated bioinformatics approach and clinical trials, which might decrease CD4+ and CD8+ T cells.

Keywords: miRNAs, adenocarcinoma, biomarkers, tumors, immunofluorescence, immune infiltration.

Cai, Z.; Liu, Q. Understanding the global cancer statistics 2018: Implications for cancer control. Sci. China Life Sci., 2021, 64(6), 1017-1020.
[] [PMID: 31463738]
Sun, Y.; Wu, X.; Zhang, Y.; Lin, H.; Lu, X.; Huang, Y.; Chi, P. Pathological complete response may underestimate distant metastasis in locally advanced rectal cancer following neoadjuvant chemoradiotherapy and radical surgery: Incidence, metastatic pattern, and risk factors. Eur. J. Surg. Oncol., 2019, 45(7), 1225-1231.
[] [PMID: 30879932]
Margalit, O.; Mamtani, R.; Kopetz, S.; Yang, Y.X.; Lawrence, Y.R.; Abu-Gazala, S.; Reiss, K.A.; Golan, T.; Halpern, N.; Aderka, D.; Giantonio, B.; Shacham-Shmueli, E.; Boursi, B. Refining the use of adjuvant oxaliplatin in clinical stage II or III rectal adenocarcinoma. Oncologist, 2019, 24(8), e671-e676.
[] [PMID: 30696723]
Demisse, R.; Damle, N.; Kim, E.; Gong, J.; Fakih, M.; Eng, C.; Oesterich, L.; McKenny, M.; Ji, J.; Liu, J.; Louie, R.; Tam, K.; Gholami, S.; Halabi, W.; Monjazeb, A.; Dayyani, F.; Cho, M. Neoadjuvant immunotherapy–based systemic treatment in MMR-deficient or MSI-high rectal cancer: Case series. J. Natl. Compr. Canc. Netw., 2020, 18(7), 798-804.
[] [PMID: 32634770]
Karagkounis, G.; Thai, L.; Mace, A.G.; Wiland, H.; Pai, R.K.; Steele, S.R.; Church, J.M.; Kalady, M.F. Prognostic implications of pathological response to neoadjuvant chemoradiation in pathologic stage III rectal cancer. Ann. Surg., 2019, 269(6), 1117-1123.
[] [PMID: 31082910]
Fernandez-Martos, C.; Brown, G.; Estevan, R.; Salud, A.; Montagut, C.; Maurel, J.; Safont, M.J.; Aparicio, J.; Feliu, J.; Vera, R.; Alonso, V.; Gallego, J.; Martin, M.; Pera, M.; Sierra, E.; Serra, J.; Delgado, S.; Roig, J.V.; Santos, J.; Pericay, C. Preoperative chemotherapy in patients with intermediate-risk rectal adenocarcinoma selected by high-resolution magnetic resonance imaging: The GEMCAD 0801 phase II multicenter trial. Oncologist, 2014, 19(10), 1042-1043.
[] [PMID: 25209376]
Uthayopas, K.; de Sá, A.G.C.; Alavi, A.; Pires, D.E.V.; Ascher, D.B. TSMDA: Target and symptom-based computational model for miRNA-disease-association prediction. Mol. Ther. Nucleic Acids, 2021, 26, 536-546.
[] [PMID: 34631283]
Moradi-Chaleshtori, M.; Shojaei, S.; Mohammadi-Yeganeh, S.; Hashemi, S.M. Transfer of miRNA in tumor-derived exosomes suppresses breast tumor cell invasion and migration by inducing M1 polarization in macrophages. Life Sci., 2021, 282, 119800.
[] [PMID: 34245773]
He, D.; Wang, H.; Ho, S.L.; Chan, H.N.; Hai, L.; He, X.; Wang, K.; Li, H.W. Total internal reflection-based single-vesicle in situ quantitative and stoichiometric analysis of tumor-derived exosomal microRNAs for diagnosis and treatment monitoring. Theranostics, 2019, 9(15), 4494-4507.
[] [PMID: 31285775]
Shelton, M.; Anene, C.A.; Nsengimana, J.; Roberts, W.; Newton-Bishop, J.; Boyne, J.R. The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma. Biochim. Biophys. Acta Rev. Cancer, 2021, 1875(1), 188456.
[] [PMID: 33153973]
Leão, R.; van Agthoven, T.; Figueiredo, A.; Jewett, M.A.S.; Fadaak, K.; Sweet, J.; Ahmad, A.E.; Anson-Cartwright, L.; Chung, P.; Hansen, A.; Warde, P.; Castelo-Branco, P.; O’Malley, M.; Bedard, P.L.; Looijenga, L.H.J.; Hamilton, R.J. Serum miRNA predicts viable disease after chemotherapy in patients with testicular nonseminoma germ cell tumor. J. Urol., 2018, 200(1), 126-135.
[] [PMID: 29474847]
Okugawa, Y.; Toiyama, Y.; Hur, K.; Yamamoto, A.; Yin, C.; Ide, S.; Kitajima, T.; Fujikawa, H.; Yasuda, H.; Koike, Y.; Okita, Y.; Hiro, J.; Yoshiyama, S.; Araki, T.; Miki, C.; McMillan, D.C.; Goel, A.; Kusunoki, M. Circulating miR-203 derived from metastatic tissues promotes myopenia in colorectal cancer patients. J. Cachexia Sarcopenia Muscle, 2019, 10(3), 536-548.
[] [PMID: 31091026]
Panagal, M. S R, S.K.; P, S.; M, B.; M, K.; Gopinathe, V.; Sivakumare, P.; Sekar, D. MicroRNA21 and the various types of myeloid leukemia. Cancer Gene Ther., 2018, 25(7-8), 161-166.
[] [PMID: 29795410]
Simeoli, R.; Montague, K.; Jones, H.R.; Castaldi, L.; Chambers, D.; Kelleher, J.H.; Vacca, V.; Pitcher, T.; Grist, J.; Al-Ahdal, H.; Wong, L.F.; Perretti, M.; Lai, J.; Mouritzen, P.; Heppenstall, P.; Malcangio, M. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat. Commun., 2017, 8(1), 1778.
[] [PMID: 29176651]
Mayourian, J.; Ceholski, D.K.; Gorski, P.A.; Mathiyalagan, P.; Murphy, J.F.; Salazar, S.I.; Stillitano, F.; Hare, J.M.; Sahoo, S.; Hajjar, R.J.; Costa, K.D. Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility. Circ. Res., 2018, 122(7), 933-944.
[] [PMID: 29449318]
Gao, Y.; Zou, T.; Liang, W.; Zhang, Z.; Qie, M. Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis. Cancer Gene Ther., 2021, 28(6), 619-633.
[] [PMID: 33139818]
Qu, K.; Zhang, X.; Lin, T.; Liu, T.; Wang, Z.; Liu, S.; Zhou, L.; Wei, J.; Chang, H.; Li, K.; Wang, Z.; Liu, C.; Wu, Z. Circulating miRNA-21-5p as a diagnostic biomarker for pancreatic cancer: Evidence from comprehensive miRNA expression profiling analysis and clinical validation. Sci. Rep., 2017, 7(1), 1692.
[] [PMID: 28490741]
Zhuang, L.; Zhang, B.; Liu, X.; Lin, L.; Wang, L.; Hong, Z.; Chen, J. Exosomal miR-21-5p derived from cisplatin-resistant SKOV3 ovarian cancer cells promotes glycolysis and inhibits chemosensitivity of its progenitor SKOV3 cells by targeting PDHA1. Cell Biol. Int., 2021, 45(10), 2140-2149.
[] [PMID: 34288231]
Liang, H.; Jiao, Z.; Rong, W.; Qu, S.; Liao, Z.; Sun, X.; Wei, Y.; Zhao, Q.; Wang, J.; Liu, Y.; Chen, X.; Wang, T.; Zhang, C.Y.; Zen, K. 3′-Terminal 2′-O-methylation of lung cancer miR-21-5p enhances its stability and association with Argonaute 2. Nucleic Acids Res., 2020, 48(13), gkaa504.
[] [PMID: 32542340]
Li, Q.; Li, B.; Li, Q.; Wei, S.; He, Z.; Huang, X.; Wang, L.; Xia, Y.; Xu, Z.; Li, Z.; Wang, W.; Yang, L.; Zhang, D.; Xu, Z. Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition. Cell Death Dis., 2018, 9(9), 854.
[] [PMID: 30154401]
Shoshan, E.; Mobley, A.K.; Braeuer, R.R.; Kamiya, T.; Huang, L.; Vasquez, M.E.; Salameh, A.; Lee, H.J.; Kim, S.J.; Ivan, C.; Velazquez-Torres, G.; Nip, K.M.; Zhu, K.; Brooks, D.; Jones, S.J.M.; Birol, I.; Mosqueda, M.; Wen, Y.; Eterovic, A.K.; Sood, A.K.; Hwu, P.; Gershenwald, J.E.; Gordon Robertson, A.; Calin, G.A.; Markel, G.; Fidler, I.J.; Bar-Eli, M. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol., 2015, 17(3), 311-321.
[] [PMID: 25686251]
Arai, T.; Kojima, S.; Yamada, Y.; Sugawara, S.; Kato, M.; Yamazaki, K.; Naya, Y.; Ichikawa, T.; Seki, N. Pirin: A potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p. Mol. Oncol., 2019, 13(2), 322-337.
[] [PMID: 30444038]
Troiano, G.; Mastrangelo, F.; Caponio, V.C.A.; Laino, L.; Cirillo, N.; Lo Muzio, L. Predictive prognostic value of tissue-based MicroRNA expression in oral squamous cell carcinoma: A systematic review and meta-analysis. J. Dent. Res., 2018, 97(7), 759-766.
[] [PMID: 29533734]
Chen, J.B.; Zhu, Y.W.; Guo, X.; Yu, C.; Liu, P.H.; Li, C.; Hu, J.; Li, H.H.; Liu, L.F.; Chen, M.F.; Chen, H.Q.; Xiong-Bing, Z. Microarray expression profiles analysis revealed lncRNA OXCT1-AS1 promoted bladder cancer cell aggressiveness via miR-455-5p/JAK1 signaling. J. Cell. Physiol., 2019, 234(8), 13592-13601.
[] [PMID: 30609030]
Li, H.; Mu, Q.; Zhang, G.; Shen, Z.; Zhang, Y.; Bai, J.; Zhang, L.; Zhou, D.; Zheng, Q.; Shi, L.; Su, W.; Yin, C.; Zhang, B. Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge. Cell Death Dis., 2020, 11(12), 1051.
[] [PMID: 33311443]
Zheng, X.; Rui, S.; Wang, X.F.; Zou, X.H.; Gong, Y.P.; Li, Z.H. circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling. J. Exp. Clin. Cancer Res., 2021, 40(1), 157.
[] [PMID: 33962657]
Wang, J.; Lu, Y.; Zeng, Y.; Zhang, L.; Ke, K.; Guo, Y. Expression profile and biological function of miR-455-5p in colorectal carcinoma. Oncol. Lett., 2019, 17(2), 2131-2140.
[] [PMID: 30675279]
Hecht, M.; Büttner-Herold, M.; Erlenbach-Wünsch, K.; Haderlein, M.; Croner, R.; Grützmann, R.; Hartmann, A.; Fietkau, R.; Distel, L.V. PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. Eur. J. Cancer, 2016, 65, 52-60.
[] [PMID: 27468145]
D’Angelo, E.; Zanon, C.; Sensi, F.; Digito, M.; Rugge, M.; Fassan, M.; Scarpa, M.; Pucciarelli, S.; Nitti, D.; Agostini, M. miR-194 as predictive biomarker of responsiveness to neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma. J. Clin. Pathol., 2018, 71(4), 344-350.
[] [PMID: 28870889]
Lv, Q.; Zou, H.; Xu, Y.; Shao, Z.; Wu, R.; Li, K.; Deng, X.; Gu, D.; Jiang, H.; Su, M.; Zou, C. Expression levels of chemokine (C-X-C motif) ligands CXCL1 and CXCL3 as prognostic biomarkers in rectal adenocarcinoma: Evidence from Gene Expression Omnibus (GEO) analyses. Bioengineered, 2021, 12(1), 3711-3725.
[] [PMID: 34269159]
Farchoukh, L.; Hartman, D.J.; Ma, C.; Celebrezze, J.; Medich, D.; Bahary, N.; Frank, M.; Pantanowitz, L.; Pai, R.K. Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma. Mod. Pathol., 2021, 34(1), 171-183.
[] [PMID: 32661298]
Zhao, H.; Wei, J.; Sun, J. Roles of TGF-β signaling pathway in tumor microenvirionment and cancer therapy. Int. Immunopharmacol., 2020, 89(Pt B), 107101.
Yang, Y.; Gu, X.; Li, Z.; Zheng, C.; Wang, Z.; Zhou, M.; Chen, Z.; Li, M.; Li, D.; Xiang, J. Whole-exome sequencing of rectal cancer identifies locally recurrent mutations in the Wnt pathway. Aging, 2021, 13(19), 23262-23283.
[] [PMID: 34642262]
Zheng, X.M.; Zhang, P.; Liu, M.H.; Chen, P.; Zhang, W.B. MicroRNA-30e inhibits adhesion, migration, invasion and cell cycle progression of prostate cancer cells via inhibition of the activation of the MAPK signaling pathway by downregulating CHRM3. Int. J. Oncol., 2019, 54(2), 443-454.
[PMID: 30483762]
Johnson, S.M.; Gulhati, P.; Rampy, B.A.; Han, Y.; Rychahou, P.G.; Doan, H.Q.; Weiss, H.L.; Evers, B.M. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J. Am. Coll. Surg., 2010, 210(5), 767-776.
Tang, Y.H.; He, G.L.; Huang, S.Z.; Zhong, K.B.; Liao, H.; Cai, L.; Gao, Y.; Peng, Z.W.; Fu, S.J. The long noncoding RNA AK002107 negatively modulates miR-140-5p and targets TGFBR1 to induce epithelial–mesenchymal transition in hepatocellular carcinoma. Mol. Oncol., 2019, 13(5), 1296-1310.
[] [PMID: 30943320]
Fujikura, K.; Akita, M.; Ajiki, T.; Fukumoto, T.; Itoh, T.; Zen, Y. Recurrent mutations in APC and CTNNB1 and activated Wnt/β-catenin signaling in intraductal papillary neoplasms of the bile duct. Am. J. Surg. Pathol., 2018, 42(12), 1674-1685.
[] [PMID: 30212390]
Yang, Y.; Li, X.J.; Li, P.; Guo, X.T. MicroRNA-145 regulates the proliferation, migration and invasion of human primary colon adenocarcinoma cells by targeting MAPK1. Int. J. Mol. Med., 2018, 42(6), 3171-3180.
[] [PMID: 30272312]
Ai, X.; Xiang, L.; Huang, Z.; Zhou, S.; Zhang, S.; Zhang, T.; Jiang, T. Overexpression of PIK3R1 promotes hepatocellular carcinoma progression. Biol. Res., 2018, 51(1), 52.
Cai, D.L.; Jin, L.P. Immune cell population in ovarian tumor microenvironment. J. Cancer, 2017, 8(15), 2915-2923.
[] [PMID: 28928882]

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