Transcriptome Analysis of MDA-MB-231 Cells Treated with Fumosorinone Isolated from Insect Pathogenic Fungi

Author(s): Zhiqin Liu, Yingchao Tian, Queting Chen, Gaotao Zhang, Chunqing Li, Du-Qiang Luo*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 4 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: In our previous study, we have isolated a new compound, named Fumosorinone (FU) from insect pathogenic fungi, and was found to inhibit proliferation, migration, and invasion of breast cancer MDA-MB-231 cells.

Objective: The aim of this study was to identify the underlying molecular mechanisms for FU effects on MDAMB- 231 cells.

Methods: After MDA-MB-231 cells were treated with FU for 48h, RNA sequencing was used to identify the effect of FU on the transcriptome of MDA-MB-231 cells. The validation of the relative expression of the selective genes was done using quantitative real-time PCR (qRT-PCR).

Results: The transcriptome results showed that 2733 genes were differentially expressed between the untreated and the FU-treated cells, including 1614 up-regulated and 1119 down-regulated genes. The multiple genes are associated with cancer cell growth, migration, and invasion. Functional analysis identified multitude of pathways related to cancer, such as cell cycle, ECM–receptor interaction, p53 signaling pathway. We selected 4 upregulated and 9 downregulated genes, which are associated with breast cancer to verify their expression using qRT-PCR. The validation showed that HSD3B1, ALOX5, AQP5, COL1A2, CCNB1, CCND1, VCAM-1, PTPN1 and PTPN11 were significantly downregulated while DUSP1, DUSP5, GADD45A, EGR1 were upregulated in FU-treated MDA-MB-231cells.

Conclusion: These aberrantly expressed genes and pathways may play pivotal roles in the anti-cancer activity of FU, and maybe potential targets of FU treatments for TNBC. Further investigations are required to evaluate the FU mechanisms of anti-cancer action in vivo.

Keywords: Transcriptome, insect pathogenic fungi, breast cancer, RNA sequencing, signaling pathway, qRT-PCR.

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Al-Mahmood, S.; Sapiezynski, J.; Garbuzenko, O.B.; Minko, T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv. Transl. Res., 2018, 8(5), 1483-1507.
[http://dx.doi.org/10.1007/s13346-018-0551-3] [PMID: 29978332]
[3]
Li, X.; Yang, J.; Peng, L.; Sahin, A.A.; Huo, L.; Ward, K.C.; O’Regan, R.; Torres, M.A.; Meisel, J.L. Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res. Treat., 2017, 161(2), 279-287.
[http://dx.doi.org/10.1007/s10549-016-4059-6] [PMID: 27888421]
[4]
Safarzadeh, E.; Sandoghchian Shotorbani, S.; Baradaran, B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv. Pharm. Bull., 2014, 4(Suppl. 1), 421-427.
[PMID: 25364657]
[5]
Luo, D.Q.; Zhang, J.; Liu, Z.Q. 2013. Protein tyrosine phosphatase inhibitor, preparation method and uses thereof. WO Patent WO/2013/174207. 2013.
[6]
Chen, C.; Cao, M.; Zhu, S.; Wang, C.; Liang, F.; Yan, L.; Luo, D. Discovery of a novel inhibitor of the protein tyrosine phosphatase Shp2. Sci. Rep., 2015, 5, 17626.
[http://dx.doi.org/10.1038/srep17626] [PMID: 26626996]
[7]
Chen, C.; Xue, T.; Fan, P.; Meng, L.; Wei, J.; Luo, D. Cytotoxic activity of Shp2 inhibitor fumosorinone in human cancer cells. Oncol. Lett., 2018, 15(6), 10055-10062.
[http://dx.doi.org/10.3892/ol.2018.8593] [PMID: 29928374]
[8]
Sun, Q.L.; Zhao, C.P.; Wang, T.Y.; Hao, X.B.; Wang, X.Y.; Zhang, X.; Li, Y.C. Expression profile analysis of long non-coding RNA associated with vincristine resistance in colon cancer cells by next-generation sequencing. Gene, 2015, 572(1), 79-86.
[http://dx.doi.org/10.1016/j.gene.2015.06.087] [PMID: 26164760]
[9]
Abassi, Y.A.; Xi, B.; Zhang, W.; Ye, P.; Kirstein, S.L.; Gaylord, M.R.; Feinstein, S.C.; Wang, X.; Xu, X. Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects. Chem. Biol., 2009, 16(7), 712-723.
[http://dx.doi.org/10.1016/j.chembiol.2009.05.011] [PMID: 19635408]
[10]
Klijn, C.; Durinck, S.; Stawiski, E.W.; Haverty, P.M.; Jiang, Z.; Liu, H.; Degenhardt, J.; Mayba, O.; Gnad, F.; Liu, J.; Pau, G.; Reeder, J.; Cao, Y.; Mukhyala, K.; Selvaraj, S.K.; Yu, M.; Zynda, G.J.; Brauer, M.J.; Wu, T.D.; Gentleman, R.C.; Manning, G.; Yauch, R.L.; Bourgon, R.; Stokoe, D.; Modrusan, Z.; Neve, R.M.; de Sauvage, F.J.; Settleman, J.; Seshagiri, S.; Zhang, Z. A comprehensive transcriptional portrait of human cancer cell lines. Nat. Biotechnol., 2015, 33(3), 306-312.
[http://dx.doi.org/10.1038/nbt.3080] [PMID: 25485619]
[11]
Haag, T.; Richter, A.M.; Schneider, M.B.; Jiménez, A.P.; Dammann, R.H. The dual specificity phosphatase 2 gene is hypermethylated in human cancer and regulated by epigenetic mechanisms. BMC Cancer, 2016, 16, 49.
[http://dx.doi.org/10.1186/s12885-016-2087-6] [PMID: 26833217]
[12]
Hou, M.F.; Chang, C.W.; Chen, F.M.; Wang, S.N.; Yang, S.F.; Chen, P.H.; Su, J.H.; Yeh, Y.T. Decreased total MKP-1 protein levels predict poor prognosis in breast cancer. World J. Surg., 2012, 36(8), 1922-1932.
[http://dx.doi.org/10.1007/s00268-012-1608-y] [PMID: 22547014]
[13]
Cretu, A.; Sha, X.; Tront, J.; Hoffman, B.; Liebermann, D.A. Stress sensor Gadd45 genes as therapeutic targets in cancer., Cancer. Ther, 2009, 7(A), 268-276.
[14]
Wang, X.W.; Zhan, Q.; Coursen, J.D.; Khan, M.A.; Kontny, H.U.; Yu, L.; Hollander, M.C.; O’Connor, P.M.; Fornace, A.J., Jr; Harris, C.C. GADD45 induction of a G2/M cell cycle checkpoint. Proc. Natl. Acad. Sci. USA, 1999, 96(7), 3706-3711.
[http://dx.doi.org/10.1073/pnas.96.7.3706] [PMID: 10097101]
[15]
Ataie-Kachoie, P.; Pourgholami, M.H.; Bahrami-B, F.; Badar, S.; Morris, D.L. Minocycline attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies. Am. J. Cancer Res., 2015, 5(2), 575-588.
[PMID: 25973298]
[16]
Thiel, G.; Cibelli, G. Regulation of life and death by the zinc finger transcription factor Egr-1. J. Cell. Physiol., 2002, 193(3), 287-292.
[http://dx.doi.org/10.1002/jcp.10178] [PMID: 12384981]
[17]
Ronski, K.; Sanders, M.; Burleson, J.A.; Moyo, V.; Benn, P.; Fang, M. Early growth response gene 1 (EGR1) is deleted in estrogen receptor-negative human breast carcinoma. Cancer, 2005, 104(5), 925-930.
[http://dx.doi.org/10.1002/cncr.21262] [PMID: 15999367]
[18]
Li, Z.L.; Liang, S.; Wang, Z.C.; Li, Y.B.; Guo, C.X.; Fang, F.; Gong, S.L.; Lin, C.H. Expression of Smac induced by the Egr1 promoter enhances the radiosensitivity of breast cancer cells. Cancer Gene Ther., 2014, 21(4), 142-149.
[http://dx.doi.org/10.1038/cgt.2014.9] [PMID: 24675512]
[19]
Moon, C.; Soria, J.C.; Jang, S.J.; Lee, J.; Obaidul Hoque, M.; Sibony, M.; Trink, B.; Chang, Y.S.; Sidransky, D.; Mao, L. Involvement of aquaporins in colorectal carcinogenesis. Oncogene, 2003, 22(43), 6699-6703.
[http://dx.doi.org/10.1038/sj.onc.1206762] [PMID: 14555983]
[20]
Jung, H.J.; Park, J.Y.; Jeon, H.S.; Kwon, T.H. Aquaporin-5: a marker protein for proliferation and migration of human breast cancer cells. PLoS One, 2011, 6(12) e28492
[http://dx.doi.org/10.1371/journal.pone.0028492] [PMID: 22145049]
[21]
Zhu, Z.; Jiao, L.; Li, T.; Wang, H.; Wei, W.; Qian, H. Expression of AQP3 and AQP5 as a prognostic marker in triple-negative breast cancer. Oncol. Lett., 2018, 16(2), 2661-2667.
[http://dx.doi.org/10.3892/ol.2018.8955] [PMID: 30013662]
[22]
Sengupta, P.K.; Smith, E.M.; Kim, K.; Murnane, M.J.; Smith, B.D. DNA hypermethylation near the transcription start site of collagen alpha2(I) gene occurs in both cancer cell lines and primary colorectal cancers. Cancer Res., 2003, 63(8), 1789-1797.
[PMID: 12702564]
[23]
Rong, L.; Huang, W.; Tian, S.; Chi, X.; Zhao, P.; Liu, F. COL1A2 is a novel biomarker to improve clinical prediction in human gastric cancer: Integrating bioinformatics and meta-analysis. Pathol. Oncol. Res., 2018, 24(1), 129-134.
[http://dx.doi.org/10.1007/s12253-017-0223-5] [PMID: 28401451]
[24]
Ma, X.J.; Dahiya, S.; Richardson, E.; Erlander, M.; Sgroi, D.C. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res., 2009, 11(1), R7.
[http://dx.doi.org/10.1186/bcr2222] [PMID: 19187537]
[25]
Ramaswamy, S.; Ross, K.N.; Lander, E.S.; Golub, T.R. A molecular signature of metastasis in primary solid tumors. Nat. Genet., 2003, 33(1), 49-54.
[http://dx.doi.org/10.1038/ng1060] [PMID: 12469122]
[26]
Gonzalez-Angulo, A.M.; Ferrer-Lozano, J.; Stemke-Hale, K.; Sahin, A.; Liu, S.; Barrera, J.A.; Burgues, O.; Lluch, A.M.; Chen, H.; Hortobagyi, G.N.; Mills, G.B.; Meric-Bernstam, F. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol. Cancer Ther., 2011, 10(6), 1093-1101.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-1089] [PMID: 21490305]
[27]
Lu, X.; Mu, E.; Wei, Y.; Riethdorf, S.; Yang, Q.; Yuan, M.; Yan, J.; Hua, Y.; Tiede, B.J.; Lu, X.; Haffty, B.G.; Pantel, K.; Massagué, J.; Kang, Y. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell, 2011, 20(6), 701-714.
[http://dx.doi.org/10.1016/j.ccr.2011.11.002] [PMID: 22137794]
[28]
Chen, Q.; Zhang, X.H.F.; Massagué, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell, 2011, 20(4), 538-549.
[http://dx.doi.org/10.1016/j.ccr.2011.08.025] [PMID: 22014578]
[29]
Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A., Jr; Kinzler, K.W. Cancer genome landscapes. Science, 2013, 339(6127), 1546-1558.
[http://dx.doi.org/10.1126/science.1235122] [PMID: 23539594]
[30]
Bertoli, C.; Skotheim, J.M.; de Bruin, R.A. Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol., 2013, 14(8), 518-528.
[http://dx.doi.org/10.1038/nrm3629] [PMID: 23877564]
[31]
Schaarschmidt, D.; Ladenburger, E.M.; Keller, C.; Knippers, R. Human Mcm proteins at a replication origin during the G1 to S phase transition. Nucleic Acids Res., 2002, 30(19), 4176-4185.
[http://dx.doi.org/10.1093/nar/gkf532] [PMID: 12364596]
[32]
Espinosa, J.M. Mechanisms of regulatory diversity within the p53 transcriptional network. Oncogene, 2008, 27(29), 4013-4023.
[http://dx.doi.org/10.1038/onc.2008.37] [PMID: 18278067]
[33]
Essmann, F.; Schulze-Osthoff, K. Translational approaches targeting the p53 pathway for anti-cancer therapy. Br. J. Pharmacol., 2012, 165(2), 328-344.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01570.x] [PMID: 21718309]
[34]
Wang, M.; Zhao, J.; Zhang, L.; Wei, F.; Lian, Y.; Wu, Y.; Gong, Z.; Zhang, S.; Zhou, J.; Cao, K.; Li, X.; Xiong, W.; Li, G.; Zeng, Z.; Guo, C. Role of tumor microenvironment in tumorigenesis. J. Cancer, 2017, 8(5), 761-773.
[http://dx.doi.org/10.7150/jca.17648] [PMID: 28382138]
[35]
Venning, F.A.; Wullkopf, L.; Erler, J.T. Targeting ECM disrupts cancer progression. Front. Oncol., 2015, 5, 224-238.
[http://dx.doi.org/10.3389/fonc.2015.00224] [PMID: 26539408]
[36]
Wu, J.Z.; Yang, T.J.; Lu, P.; Ma, W. Analysis of signaling pathways in recurrent breast cancer. Genet. Mol. Res., 2014, 13(4), 10097-10104.
[http://dx.doi.org/10.4238/2014.December.4.4] [PMID: 25501221]
[37]
Kim, B.G.; An, H.J.; Kang, S.; Choi, Y.P.; Gao, M.Q.; Park, H.; Cho, N.H. Laminin-332-rich tumor microenvironment for tumor invasion in the interface zone of breast cancer. Am. J. Pathol., 2011, 178(1), 373-381.
[http://dx.doi.org/10.1016/j.ajpath.2010.11.028] [PMID: 21224074]
[38]
Cardoso, M.R.; Santos, J.C.; Ribeiro, M.L.; Talarico, M.C.R.; Viana, L.R.; Derchain, S.F.M. A metabolomic approach to predict breast cancer behavior and chemotherapy response. Int. J. Mol. Sci., 2018, 19(2) E617
[http://dx.doi.org/10.3390/ijms19020617] [PMID: 29466297]
[39]
O’Flanagan, C.H.; Rossi, E.L.; McDonell, S.B.; Chen, X.; Tsai, Y.H.; Parker, J.S.; Usary, J.; Perou, C.M.; Hursting, S.D. Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer. NPJ Breast Cancer, 2017, 3, 26.
[http://dx.doi.org/10.1038/s41523-017-0027-5] [PMID: 28748213]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 4
Year: 2020
Published on: 14 May, 2020
Page: [417 - 428]
Pages: 12
DOI: 10.2174/1871520619666191212150322
Price: $65

Article Metrics

PDF: 28
HTML: 8
EPUB: 1
PRC: 1