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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

General Research Article

Clinical and In Silico Outcomes of the Expression of miR-130a-5p and miR-615-3p in Tumor Compared with Non-Tumor Adjacent Tissues of Patients with BC

Author(s): Khandan Ilkhani, Soheila Delgir, Asma Safi, Farhad Seif, Azam Samei, Milad Bastami* and Mohammad Reza Alivand*

Volume 21 , Issue 7 , 2021

Published on: 24 September, 2020

Page: [927 - 935] Pages: 9

DOI: 10.2174/1871520620666200924105352

Price: $65


Background: Breast Cancer (BC) is the most common malignancy among women with a high mortality rate. The blockade of asparagine-related pathways may be an effective measure to control the progression and reduction of BC metastasis potential. Recently, it has been shown that various miRNAs, as part of small non-coding RNAs, have a great role in cancer development, especially asparagine-related pathways, to modulate the invasiveness.

Objective: This study aimed to evaluate the expression of miR-130a-5p and miR-615-3p in tumoral and nontumoral adjacent tissues of patients with BC.

Methods: There is a chance that asparagine metabolism is influenced by miR-130a-5p and miR-615-3p as confirmed by bioinformatics analysis. Hence, real-time PCR was conducted on eighty BC tumoral and non-tumoral adjacent tissues to evaluate the expression level of the two miRNAs. To predict the potential biological process and molecular pathways of miR-130a-5p, an in silico analysis was performed.

Results: This study indicated that miR-130a was downregulated in tumoral tissues compared to non-tumoral adjacent tissues (P-value= 0.01443 and fold change= -2.5137), while miR-615-3p did not show a significant difference between the two groups. Furthermore, the subgroup studies did not reveal any significant correlation between the expression of these two miRNAs and subfactors. Furthermore, in silico studies unraveled several biological processes related to amino-acid metabolism, as well as pathways related to tumor development such as Phosphatase and Tensin Homolog (PTEN) and JAK-STAT pathways among miR-130a-5p target genes.

Conclusion: Our findings indicate that miRNA-130a-5p is downregulated in BC tissues and may play a tumor suppressor role in patients with BC. Therefore, it may be suggested as a potential diagnostic and therapeutic target for BC.

Keywords: Breast cancer, cancer metabolism, asparagine synthetase, microRNA, PTEN signaling pathway, JAK-STAT pathway.

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De Leeneer, K.; Claes, K. Non coding RNA molecules as potential biomarkers in breast cancer. Adv. Exp. Med. Biol., 2015, 867, 263-275.
[] [PMID: 26530371]
Abtin, M.; Alivand, M.R.; Khaniani, M.S.; Bastami, M.; Zaeifizadeh, M.; Derakhshan, S.M. Simultaneous downregulation of miR-21 and miR-155 through oleuropein for breast cancer prevention and therapy. J. Cell. Biochem., 2018, 119(9), 7151-7165.
[] [PMID: 29905007]
Bononi, A.; Yang, H.; Giorgi, C.; Patergnani, S.; Pellegrini, L.; Su, M.; Xie, G.; Signorato, V.; Pastorino, S.; Morris, P.; Sakamoto, G.; Kuchay, S.; Gaudino, G.; Pass, H.I.; Napolitano, A.; Pinton, P.; Jia, W.; Carbone, M. Germline BAP1 mutations induce a Warburg effect. Cell Death Differ., 2017, 24(10), 1694-1704.
[] [PMID: 28665402]
Zhang, J.; Fan, J.; Venneti, S.; Cross, J.R.; Takagi, T.; Bhinder, B.; Djaballah, H.; Kanai, M.; Cheng, E.H.; Judkins, A.R.; Pawel, B.; Baggs, J.; Cherry, S.; Rabinowitz, J.D.; Thompson, C.B. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell, 2014, 56(2), 205-218.
[] [PMID: 25242145]
Hettmer, S.; Schinzel, A.C.; Tchessalova, D.; Schneider, M.; Parker, C.L.; Bronson, R.T.; Richards, N.G.; Hahn, W.C.W.A.; Wagers, A.J. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. eLife, 2015, 4, e09436.
[] [PMID: 26499495]
Mauro-Lizcano, M.; López-Rivas, A. Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells. Cell Death Dis., 2018, 9(2), 205.
[] [PMID: 29434187]
Yang, H.; He, X.; Zheng, Y.; Feng, W.; Xia, X.; Yu, X.; Lin, Z. Down-regulation of asparagine synthetase induces cell cycle arrest and inhibits cell proliferation of breast cancer. Chem. Biol. Drug Des., 2014, 84(5), 578-584.
[] [PMID: 24775638]
Sircar, K.; Huang, H.; Hu, L.; Cogdell, D.; Dhillon, J.; Tzelepi, V.; Efstathiou, E.; Koumakpayi, I.H.; Saad, F.; Luo, D.; Bismar, T.A.; Aparicio, A.; Troncoso, P.; Navone, N.; Zhang, W. Integrative molecular profiling reveals asparagine synthetase is a target in castration-resistant prostate cancer. Am. J. Pathol., 2012, 180(3), 895-903.
[] [PMID: 22245216]
Xu, Y.; Lv, F.; Zhu, X.; Wu, Y.; Shen, X. Loss of asparagine synthetase suppresses the growth of human lung cancer cells by arresting cell cycle at G0/G1 phase. Cancer Gene Ther., 2016, 23(9), 287-294.
[] [PMID: 27444726]
Pui, C-H.; Robison, L.L.; Look, A.T. Acute lymphoblastic leukaemia. Lancet, 2008, 371(9617), 1030-1043.
[] [PMID: 18358930]
Luo, M.; Brooks, M.; Wicha, M.S. Asparagine and glutamine: Co-conspirators fueling metastasis. Cell Metab., 2018, 27(5), 947-949.
[] [PMID: 29719230]
Krall, A.S.; Xu, S.; Graeber, T.G.; Braas, D.; Christofk, H.R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun., 2016, 7(1), 11457.
[] [PMID: 27126896]
Li, H.; Zhou, F.; Du, W.; Dou, J.; Xu, Y.; Gao, W.; Chen, G.; Zuo, X.; Sun, L.; Zhang, X.; Yang, S. Knockdown of asparagine synthetase by RNAi suppresses cell growth in human melanoma cells and epidermoid carcinoma cells. Biotechnol. Appl. Biochem., 2016, 63(3), 328-333.
[] [PMID: 25858017]
Zhu, Y.; Li, T.; Ramos da Silva, S.; Lee, J-J.; Lu, C.; Eoh, H.; Jung, J.U.; Gao, S.J. A critical role of glutamine and asparagine γ-Nitrogen in nucleotide biosynthesis in cancer cells hijacked by an oncogenic virus. MBio, 2017, 8(4), e01179-e17.
[] [PMID: 28811348]
Jiang, J.; Srivastava, S.; Seim, G.; Pavlova, N.N.; King, B.; Zou, L.; Zhang, C.; Zhong, M.; Feng, H.; Kapur, R.; Wek, R.C.; Fan, J.; Zhan, J. Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion. J. Biol. Chem., 2017, 39(2), 18674-18684.
Zhu, W.; Radadiya, A.; Bisson, C.; Nordin, B.E.; Baumann, P.; Imasaki, T. Molecular basis of human asparagine synthetase inhibitor specificity. bioRxiv, 2018, 428508
Agarwal, V.; Bell, G.W.; Nam, J-W.; Bartel, D.P. Predicting effective microRNA target sites in mammalian mRNAs. eLife, 2015, 4, e05005.
[] [PMID: 26267216]
Chou, C-H.; Shrestha, S.; Yang, C.D.; Chang, N.W.; Lin, Y.L.; Liao, K.W.; Huang, W.C.; Sun, T.H.; Tu, S.J.; Lee, W.H.; Chiew, M.Y.; Tai, C.S.; Wei, T.Y.; Tsai, T.R.; Huang, H.T.; Wang, C.Y.; Wu, H.Y.; Ho, S.Y.; Chen, P.R.; Chuang, C.H.; Hsieh, P.J.; Wu, Y.S.; Chen, W.L.; Li, M.J.; Wu, Y.C.; Huang, X.Y.; Ng, F.L.; Buddhakosai, W.; Huang, P.C.; Lan, K.C.; Huang, C.Y.; Weng, S.L.; Cheng, Y.N.; Liang, C.; Hsu, W.L.; Huang, H.D. miRTarBase update 2018: A resource for experimentally validated microRNA-target interactions. Nucleic Acids Res., 2018, 46(D1), D296-D302.
[] [PMID: 29126174]
Liu, Z.; Wang, J.; Li, Y.; Fan, J.; Chen, L.; Xu, R. MicroRNA-153 regulates glutamine metabolism in glioblastoma through targeting glutaminase. Tumour Biol., 2017, 39(2)
[] [PMID: 28218035]
Song, L-J.; Zhang, W-J.; Chang, Z-W.; Pan, Y-F.; Zong, H.; Fan, Q-X.; Wang, L.X.P.U. 1 is identified as a novel metastasis suppressor in hepatocellular carcinoma regulating the miR-615-5p/IGF2 axis. Asian Pac. J. Cancer Prev., 2015, 16(9), 3667-3671.
[] [PMID: 25987019]
Wu, X.; Deng, L.; Tang, D.; Ying, G.; Yao, X.; Liu, F.; Liang, G. miR-615-5p prevents proliferation and migration through negatively regulating Serine Hydromethyltransferase 2 (SHMT2) in hepatocellular carcinoma. Tumour Biol., 2016, 37(5), 6813-6821.
[] [PMID: 26662310]
Bai, Y.; Li, J.; Li, J.; Liu, Y.; Zhang, B. MiR-615 inhibited cell proliferation and cell cycle of human breast cancer cells by suppressing of AKT2 expression. Int. J. Clin. Exp. Med., 2015, 8(3), 3801-3808.
[PMID: 26064277]
Huang, F.; Zhao, H.; Du, Z.; Jiang, H. miR-615 inhibits prostate cancer cell proliferation and invasion by directly targeting cyclin D2. Oncol. Res., 2019, 27(3), 293-299.
[] [PMID: 29471894]
Ji, Y.; Sun, Q.; Zhang, J.; Hu, H. MiR-615 inhibits cell proliferation, migration and invasion by targeting EGFR in human glioblastoma. Biochem. Biophys. Res. Commun., 2018, 499(3), 719-726.
[] [PMID: 29605294]
Gao, W.; Gu, Y.; Li, Z.; Cai, H.; Peng, Q.; Tu, M.; Kondo, Y.; Shinjo, K.; Zhu, Y.; Zhang, J.; Sekido, Y.; Han, B.; Qian, Z.; Miao, Y. miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene, 2015, 34(13), 1629-1640.
[] [PMID: 24769899]
Ouyang, M.; Li, Y.; Ye, S.; Ma, J.; Lu, L.; Lv, W.; Chang, G.; Li, X.; Li, Q.; Wang, S.; Wang, W. MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer. PLoS One, 2014, 9(5), e96228.
[] [PMID: 24788655]
Stückrath, I.; Rack, B.; Janni, W.; Jäger, B.; Pantel, K.; Schwarzenbach, H. Aberrant plasma levels of circulating miR-16, miR-107, miR-130a and miR-146a are associated with lymph node metastasis and receptor status of breast cancer patients. Oncotarget, 2015, 6(15), 13387-13401.
[] [PMID: 26033453]
Ye, L.; Wang, Y.; Nie, L.; Qian, S.; Xu, M. MiR-130 exerts tumor suppressive function on the tumorigenesis of human non-small cell lung cancer by targeting PTEN. Am. J. Transl. Res., 2017, 9(4), 1856-1865.
[PMID: 28469790]
Duan, J.; Zhang, H.; Qu, Y.; Deng, T.; Huang, D.; Liu, R.; Zhang, L.; Bai, M.; Zhou, L.; Ying, G.; Ba, Y. Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer. Oncotarget, 2016, 7(28), 44522-44533.
[] [PMID: 27304191]
Lee, S.H.; Jung, Y.D.; Choi, Y.S.; Lee, Y.M. Targeting of RUNX3 by miR-130a and miR-495 cooperatively increases cell proliferation and tumor angiogenesis in gastric cancer cells. Oncotarget, 2015, 6(32), 33269-33278.
[] [PMID: 26375442]
Yang, L.; Li, N.; Wang, H.; Jia, X.; Wang, X.; Luo, J. Altered microRNA expression in cisplatin-resistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance. Oncol. Rep., 2012, 28(2), 592-600.
[] [PMID: 22614869]
Egawa, H.; Jingushi, K.; Hirono, T.; Ueda, Y.; Kitae, K.; Nakata, W.; Fujita, K.; Uemura, M.; Nonomura, N.; Tsujikawa, K. The miR-130 family promotes cell migration and invasion in bladder cancer through FAK and Akt phosphorylation by regulating PTEN. Sci. Rep., 2016, 6(1), 20574.
[] [PMID: 26837847]
Knott, S.R.V.; Wagenblast, E.; Khan, S.; Kim, S.Y.; Soto, M.; Wagner, M.; Turgeon, M.O.; Fish, L.; Erard, N.; Gable, A.L.; Maceli, A.R.; Dickopf, S.; Papachristou, E.K.; D’Santos, C.S.; Carey, L.A.; Wilkinson, J.E.; Harrell, J.C.; Perou, C.M.; Goodarzi, H.; Poulogiannis, G.; Hannon, G.J. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature, 2018, 554(7692), 378-381.
[] [PMID: 29414946]
Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 2005, 120(1), 15-20.
[] [PMID: 15652477]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[] [PMID: 19131956]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res., 2009, 37(1), 1-13.
[] [PMID: 19033363]
Liao, Y.; Wang, J.; Jaehnig, E.J.; Shi, Z.; Zhang, B. WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res., 2019, 47(W1), W199-W205.
[] [PMID: 31114916]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.IT Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
Bahrami, A.; Aledavood, A.; Anvari, K.; Hassanian, S.M.; Maftouh, M.; Yaghobzade, A.; Salarzaee, O. ShahidSales, S.; Avan, A. The prognostic and therapeutic application of microRNAs in breast cancer: Tissue and circulating microRNAs. J. Cell. Physiol., 2018, 233(2), 774-786.
[] [PMID: 28109133]
Louie, S.M.; Grossman, E.A.; Crawford, L.A.; Ding, L.; Camarda, R.; Huffman, T.R.; Miyamoto, D.K.; Goga, A.; Weerapana, E.; Nomura, D.K. GSTP1 is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chem. Biol., 2016, 23(5), 567-578.
[] [PMID: 27185638]
Schwartz, L.; Seyfried, T.; Alfarouk, K.O.; Da Veiga Moreira, J.; Fais, S. Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin. Cancer Biol., 2017, 43, 134-138.
[] [PMID: 28122260]
Pan, Y.; Wang, R.; Zhang, F.; Chen, Y.; Lv, Q.; Long, G.; Yang, K. MicroRNA-130a inhibits cell proliferation, invasion and migration in human breast cancer by targeting the RAB5A. Int. J. Clin. Exp. Pathol., 2015, 8(1), 384-393.
[PMID: 25755726]
Huang, J.; Zhao, M.; Hu, H.; Wang, J.; Ang, L.; Zheng, L. MicroRNA-130a reduces drug resistance in breast cancer. Int. J. Clin. Exp. Pathol., 2019, 12(7), 2699-2705.
[PMID: 31934100]
Liu, L.; Nie, J.; Chen, L.; Dong, G.; Du, X.; Wu, X.; Tang, Y.; Han, W. The oncogenic role of microRNA-130a/301a/454 in human colorectal cancer via targeting Smad4 expression. PLoS One, 2013, 8(2), e55532.
[] [PMID: 23393589]
Lu, K.; Shen, H.; Zhu, S.; Bi, S.; Wu, S. Effects of miRNA-130a on the proliferation and apoptosis of glioma cell lines. Oncol. Lett., 2018, 16(2), 2478-2482.
[] [PMID: 30013640]
Lee, Y-R.; Chen, M.; Lee, J.D.; Zhang, J.; Lin, S-Y.; Fu, T-M. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science, 2019, 364(6441), eaau0159.
Su, R.; Nan, H.; Guo, H.; Ruan, Z.; Jiang, L.; Song, Y.; Nan, K. Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma. Hepatol. Res., 2016, 46(13), 1380-1391.
[] [PMID: 26932478]
Wise, H.M.; Hermida, M.A.; Leslie, N.R. Prostate cancer, PI3K, PTEN and prognosis. Clin. Sci. (Lond.), 2017, 131(3), 197-210.
[] [PMID: 28057891]
Zhihong, Z.; Rubin, C.; Liping, L.; Anpeng, M.; Hui, G.; Yanting, W.; Zhenxiu, S. MicroRNA-1179 regulates proliferation and chemosensitivity of human ovarian cancer cells by targeting the PTEN-mediated PI3K/AKT signaling pathway. Arch. Med. Sci., 2019, 16(4), 907-914.
[] [PMID: 32542094]
Li, N.; Yang, L.; Wang, H.; Yi, T.; Jia, X.; Chen, C.; Xu, P. miR-130a and miR-374a function as novel regulators of cisplatin resistance in human ovarian cancer A2780 cells. PLoS One, 2015, 10(6), e0128886.
[] [PMID: 26043084]
Luo, N. Role of JAK-STAT pathway in cancer signaling; Predict. Biomarkers Oncol, 2019, pp. 311-319.
Groner, B.; von Manstein, V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol. Cell. Endocrinol., 2017, 451, 1-14.
[] [PMID: 28576744]
Dolatabadi, S.; Jonasson, E.; Lindén, M.; Fereydouni, B.; Bäcksten, K.; Nilsson, M.; Martner, A.; Forootan, A.; Fagman, H.; Landberg, G.; Åman, P.; Ståhlberg, A. JAK-STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma. Int. J. Cancer, 2019, 145(2), 435-449.
[] [PMID: 30650179]
Seif, F.; Khoshmirsafa, M.; Aazami, H.; Mohsenzadegan, M.; Sedighi, G.; Bahar, M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun. Signal., 2017, 15(1), 23.
[] [PMID: 28637459]
Seif, F.; Aazami, H.; Khoshmirsafa, M.; Kamali, M.; Mohsenzadegan, M.; Pornour, M.; Mansouri, D. JAK inhibition as a new treatment strategy for patients with COVID-19. Int. Arch. Allergy Immunol., 2020, 181(6), 467-475.
[] [PMID: 32392562]
Knutti, N.; Huber, O.; Friedrich, K. CD147 (EMMPRIN) controls malignant properties of breast cancer cells by interdependent signaling of Wnt and JAK/STAT pathways. Mol. Cell. Biochem., 2019, 451(1-2), 197-209.
[] [PMID: 30022447]
Lee, J.H.; Kim, C.; Baek, S.H.; Ko, J.H.; Lee, S.G.; Yang, W.M.; Um, J.Y.; Sethi, G.; Ahn, K.S. Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer. Oncotarget, 2017, 8(11), 17700-17711.
[] [PMID: 27458171]
Zhang, C.S.; Lin, Y.; Sun, F.B.; Gao, J.; Han, B.; Li, S.J. miR-409 down-regulates JAK-STAT pathway to inhibit progression of liver cancer. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(1), 146-154.
[PMID: 30657556]
Tang, S.; Yuan, X.; Song, J.; Chen, Y.; Tan, X.; Li, Q. Association analyses of the JAK/STAT signaling pathway with the progression and prognosis of colon cancer. Oncol. Lett., 2019, 17(1), 159-164.
[PMID: 30655751]
Yang, B.; Xie, R.; Wu, S.N.; Gao, C.C.; Yang, X.Z.; Zhou, J.F. MicroRNA-615-5p targets insulin-like growth factor 2 and exerts tumor-suppressing functions in human esophageal squamous cell carcinoma. Oncol. Rep., 2018, 39(1), 255-263.
[PMID: 29115555]
Jiang, Y.; Zhang, Y.; Li, F.; Du, X.; Zhang, J. CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p. Tumour Biol., 2016, 37(1), 1041-1049.
[] [PMID: 26269116]

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