Molecule Information

General Information of the Molecule (ID: Mol04366)

• Name: Signal transducer and activator of transcription 3 (STAT3) ,Homo sapiens
• Synonyms: Acute-phase response factor
• Molecule Type: Protein
• Gene Name: STAT3
• Gene ID: 6774
• Sequence:
  MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNL
  LGEIDQQYSRFLQESNVLYQHNLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTA
  A TAAQQGGQANHPTAAVVTEKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKT
  LK SQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTD
  EEL ADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGD
  PIVQ HRPMLEERIVELFRNLMKSAFVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKF
  PELNY QLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESNNGSLSAEFKHLTLR
  EQRCGN GGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNA
  WASILWY NMLTNNPKNVNFFTKPPIGTWDQVAEVLSWQFSSTTKRGLSIEQLTTLAEKL
  LGPGVNYS GCQITWAKFCKENMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISK
  ERERAILST KPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQLNNMSF
  AEIIMGYKIM DATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGSAAPYLKTK
  FICVTPTTCSN TIDLPMSPRTLDSLMQFGNNGEGAEPSAGGQFESLTFDMELTSECATS
  PM
• Function: Signal transducer and transcription activator that mediatescellular responses to interleukins, KITLG/SCF, LEP and other growthfactors . Once activated,recruits coactivators, such as NCOA1 or MED1, to the promoter region ofthe target gene . May mediatecellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Upon activation of IL6ST/gp130 signaling byinterleukin-6 , binds to the IL6-responsive elements identified inthe promoters of various acute-phase protein genes .Activated by IL31 through IL31RA . Acts as a regulatorof inflammatory response by regulating differentiation of naive CD4T-cells into T-helper Th17 or regulatory T-cells : acetylationpromotes its transcription activity and cell differentiation whiledeacetylation and oxidation of lysine residues by LOXL3 inhibitsdifferentiation . Involved in cellcycle regulation by inducing the expression of key genes for theprogression from G1 to S phase, such as CCND1 .Mediates the effects of LEP on melanocortin production, body energyhomeostasis and lactation . May play an apoptotic roleby transctivating BIRC5 expression under LEP activation. Cytoplasmic STAT3 represses macroautophagy byinhibiting EIF2AK2/PKR activity . Plays a crucial rolein basal beta cell functions, such as regulation of insulin secretion. Following JAK/STAT signaling activation and as part ofa complex with NFATC3 and NFATC4, binds to the alpha-beta E4 promoterregion of CRYAB and activates transcription in cardiomyocytes . {ECO:0000250|UniProtKB:P42227,ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:12359225,ECO:0000269|PubMed:12873986, ECO:0000269|PubMed:15194700,ECO:0000269|PubMed:15653507, ECO:0000269|PubMed:16285960,ECO:0000269|PubMed:17344214, ECO:0000269|PubMed:18242580,ECO:0000269|PubMed:18782771, ECO:0000269|PubMed:22306293,ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:28065600,ECO:0000269|PubMed:28262505, ECO:0000269|PubMed:32929201,ECO:0000269|PubMed:38404237}.
• Uniprot ID: STAT3_HUMAN
• Ensembl ID: ENSG0000016861017
• HGNC ID: HGNC:11364

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Caco2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Cetuximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

References

• Ref 1: HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway. Discov Oncol. 2024 Oct 29;15(1):603.