Molecule Information

General Information of the Molecule (ID: Mol00196)

• Name: Zinc finger E-box-binding homeobox 2 (ZEB2) ,Homo sapiens
• Synonyms: Smad-interacting protein 1; SMADIP1; Zinc finger homeobox protein 1b; KIAA0569; SIP1; ZFHX1B; ZFX1B; HRIHFB2411
• Molecule Type: Protein
• Gene Name: ZEB2
• Gene ID: 9839
• Location: chr2:144364364-144521057[-]
• Sequence:
  MKQPIMADGPRCKRRKQANPRRKNVVNYDNVVDTGSETDEEDKLHIAEDDGIANPLDQET
  SPASVPNHESSPHVSQALLPREEEEDEIREGGVEHPWHNNEILQASVDGPEEMKEDYDTM
  GPEATIQTAINNGTVKNANCTSDFEEYFAKRKLEERDGHAVSIEEYLQRSDTAIIYPEAP
  EELSRLGTPEANGQEENDLPPGTPDAFAQLLTCPYCDRGYKRLTSLKEHIKYRHEKNEEN
  FSCPLCSYTFAYRTQLERHMVTHKPGTDQHQMLTQGAGNRKFKCTECGKAFKYKHHLKEH
  LRIHSGEKPYECPNCKKRFSHSGSYSSHISSKKCIGLISVNGRMRNNIKTGSSPNSVSSS
  PTNSAITQLRNKLENGKPLSMSEQTGLLKIKTEPLDFNDYKVLMATHGFSGTSPFMNGGL
  GATSPLGVHPSAQSPMQHLGVGMEAPLLGFPTMNSNLSEVQKVLQIVDNTVSRQKMDCKA
  EEISKLKGYHMKDPCSQPEEQGVTSPNIPPVGLPVVSHNGATKSIIDYTLEKVNEAKACL
  QSLTTDSRRQISNIKKEKLRTLIDLVTDDKMIENHNISTPFSCQFCKESFPGPIPLHQHE
  RYLCKMNEEIKAVLQPHENIVPNKAGVFVDNKALLLSSVLSEKGMTSPINPYKDHMSVLK
  AYYAMNMEPNSDELLKISIAVGLPQEFVKEWFEQRKVYQYSNSRSPSLERSSKPLAPNSN
  PPTKDSLLPRSPVKPMDSITSPSIAELHNSVTNCDPPLRLTKPSHFTNIKPVEKLDHSRS
  NTPSPLNLSSTSSKNSHSSSYTPNSFSSEELQAEPLDLSLPKQMKEPKSIIATKNKTKAS
  SISLDHNSVSSSSENSDEPLNLTFIKKEFSNSNNLDNKSTNPVFSMNPFSAKPLYTALPP
  QSAFPPATFMPPVQTSIPGLRPYPGLDQMSFLPHMAYTYPTGAATFADMQQRRKYQRKQG
  FQGELLDGAQDYMSGLDDMTDSDSCLSRKKIKKTESGMYACDLCDKTFQKSSSLLRHKYE
  HTGKRPHQCQICKKAFKHKHHLIEHSRLHSGEKPYQCDKCGKRFSHSGSYSQHMNHRYSY
  CKREAEEREAAEREAREKGHLEPTELLMNRAYLQSITPQGYSDSEERESMPRDGESEKEH
  EKEGEDGYGKLGRQDGDEEFEEEEEESENKSMDTDPETIRDEEETGDHSMDDSSEDGKME
  TKSDHEEDNMEDGM
• Function: Transcriptional inhibitor that binds to DNA sequence 5'-CACCT-3' in different promoters. Represses transcription of E-cadherin. Represses expression of MEOX2.
• Uniprot ID: ZEB2_HUMAN
• Ensembl ID: ENSG00000169554
• HGNC ID: HGNC:14881

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Missense mutation; p.Y663C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Lung adenocarcinoma [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Direct interaction between miR203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance. ZEB2 was found to be a direct target of miR203, which induces epithelial-mesenchymal transition (EMT) signal.

Disease Class: Lung small cell carcinoma [3]

• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-200b was down-regulated in the resistant cells and enforced expression of miR-200b by miRNA mimics increased cell sensitivity. Overexpression of miR-200b led to the downregulation of ZEB2 at protein level. Luciferase reporter gene assay showed that 3'UTR ZEB2 activity was regulated by miR-200b. ZEB2 modulates drug resistance and is regulated by miR-200b. knockdown of ZEB2 increased cell sensitivity through increasing drug-induced cell apoptosis accompanied with S phase arrest. ZEB2 was regulated by miR-200b at protein level.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [4]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ZEB2 signaling pathway; Inhibition; hsa05202
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c regulates cisplatin resistance by targeting ZEB2 in human gastric cancer cells.

Disease Class: Nasopharyngeal carcinoma [5]

• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: There is a directly negative feedback loop between miR203 and ZEB2 participating in tumor stemness and chemotherapy resistance.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast cancer [6]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: MCF-10-2A cells; Breast; Homo sapiens (Human); CVCL_3743
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter-blue cell viability assay
• Mechanism Description: The up-regulation of the miR-200b and miR-200c diminishes EMT by directly targeting the transcriptional repressor ZEB1 leading to up-regulation of E-cadherin. Restoration of E-cadherin expression increases the sensitivity of cancer cells to chemotherapeutic agents. Disruption of ZEB1-histone deacetylase repressor complexes and down-regulation of histone deacetylase, in particular SIRT1, positively affect the p53 apoptotic pathway leading to the increased sensitivity of breast cancer cells to chemotherapy and radiotherapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [7]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Regulation; hsa04210
• Cell Pathway Regulation: RhoC/FAKT/Src/ROCK2 signaling pathways; Regulation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• Experiment for Molecule Alteration: Western blot analysis; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 sensitizes NSCLC cells to ADM through regulation of EMT regulator ZEB2. Ectopic expression of miR-138 decreased ZEB2 expression and inhibited the luciferase activity in chemoresistant tumor cells, suggesting that miR-138 could regulate EMT, at least partly, through targeting ZEB2 in NSCLC cells.

Epothilone B

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Endometrial cancer [8]

• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Sensitive Drug: Epothilone B
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hec50 cells; Endometrium; Homo sapiens (Human); CVCL_2929
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: ELISA assay
• Mechanism Description: Low or absent miR-200c results in aberrant expression of ZEB1 and consequent repression of E-cadherin. Reinstatement of miR-200c to such cells restores E-cadherin and dramatically reduces migration and invasion. One such gene, class IIIbeta-tubulin (TUBB3), which encodes a tubulin isotype normally found only in neuronal cells, is a direct target of miR-200c. Restoration of miR-200c increases sensitivity to microtubule-targeting agents by up to 85%. Since expression of TUBB3 is a common mechanism of resistance to microtubule-binding chemotherapeutic agents in many types of solid tumors, the ability of miR-200c to restore chemosensitivity to such agents may be explained by its ability to reduce TUBB3.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Endometrial cancer [8]

• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hec50 cells; Endometrium; Homo sapiens (Human); CVCL_2929
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: ELISA assay
• Mechanism Description: Low or absent miR-200c results in aberrant expression of ZEB1 and consequent repression of E-cadherin. Reinstatement of miR-200c to such cells restores E-cadherin and dramatically reduces migration and invasion. One such gene, class IIIbeta-tubulin (TUBB3), which encodes a tubulin isotype normally found only in neuronal cells, is a direct target of miR-200c. Restoration of miR-200c increases sensitivity to microtubule-targeting agents by up to 85%. Since expression of TUBB3 is a common mechanism of resistance to microtubule-binding chemotherapeutic agents in many types of solid tumors, the ability of miR-200c to restore chemosensitivity to such agents may be explained by its ability to reduce TUBB3.

Tamoxifen

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast cancer [9]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Tamoxifen
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The miR205-5p and miR200 families can silence ZEB1 and ZEB2 expression. LncRNA-ROR functions as a molecular sponge for miR205-5p and affects the target genes ZEB1 and ZEB2, which in turn influences the EMT process in breast cancer cells.

Vincristine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Endometrial cancer [8]

• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Sensitive Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hec50 cells; Endometrium; Homo sapiens (Human); CVCL_2929
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: ELISA assay
• Mechanism Description: Low or absent miR-200c results in aberrant expression of ZEB1 and consequent repression of E-cadherin. Reinstatement of miR-200c to such cells restores E-cadherin and dramatically reduces migration and invasion. One such gene, class IIIbeta-tubulin (TUBB3), which encodes a tubulin isotype normally found only in neuronal cells, is a direct target of miR-200c. Restoration of miR-200c increases sensitivity to microtubule-targeting agents by up to 85%. Since expression of TUBB3 is a common mechanism of resistance to microtubule-binding chemotherapeutic agents in many types of solid tumors, the ability of miR-200c to restore chemosensitivity to such agents may be explained by its ability to reduce TUBB3.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.37E-01; Fold-change: -6.12E-02; Z-score: -1.88E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.81E-01; Fold-change: -2.39E-01; Z-score: -5.08E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.68E-67; Fold-change: -9.50E-01; Z-score: -1.93E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.78E-39; Fold-change: -1.01E+00; Z-score: -1.69E+00

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.51E-22; Fold-change: -9.55E-01; Z-score: -8.00E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.54E-04; Fold-change: -5.20E-01; Z-score: -4.41E-01

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.36E-03; Fold-change: -1.83E+00; Z-score: -2.11E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.40E-03; Fold-change: -9.62E-01; Z-score: -1.06E+00

References

• Ref 1: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 2: Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance. Acta Biochim Biophys Sin (Shanghai). 2016 Nov;48(11):1042-1049. doi: 10.1093/abbs/gmw099. Epub 2016 Oct 12.
• Ref 3: Zinc finger E-box-binding homeobox 2 (ZEB2) regulated by miR-200b contributes to multi-drug resistance of small cell lung cancer. Exp Mol Pathol. 2014 Jun;96(3):438-44. doi: 10.1016/j.yexmp.2014.04.008. Epub 2014 Apr 22.
• Ref 4: MicroRNA-200c regulates cisplatin resistance by targeting ZEB2 in human gastric cancer cells. Oncol Rep. 2017 Jul;38(1):151-158. doi: 10.3892/or.2017.5659. Epub 2017 May 22.
• Ref 5: A directly negative interaction of miR-203 and ZEB2 modulates tumor stemness and chemotherapy resistance in nasopharyngeal carcinoma. Oncotarget. 2016 Oct 11;7(41):67288-67301. doi: 10.18632/oncotarget.11691.
• Ref 6: E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer. 2010 Jun 1;126(11):2575-83. doi: 10.1002/ijc.24972.
• Ref 7: MicroRNA-138 regulates chemoresistance in human non-small cell lung cancer via epithelial mesenchymal transition. Eur Rev Med Pharmacol Sci. 2016;20(6):1080-6.
• Ref 8: MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol Cancer Ther. 2009 May;8(5):1055-66. doi: 10.1158/1535-7163.MCT-08-1046. Epub 2009 May 12.
• Ref 9: Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother Pharmacol. 2017 Feb;79(2):327-337. doi: 10.1007/s00280-016-3208-2. Epub 2017 Jan 6.