title: KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway.
abstract: It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams-Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.
authors.affiliation: College of Life Science, North China University of Science and Technology, Tangshan, 063000, China.|Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Hospital of The North China University of Science and Technology, Tangshan, 063000, China.|Department of Nephrology, Affiliated Kailuan General Hospital of North China University of Science and Technology, Tangshan, 063000, China.
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: College of Life Science, North China University of Science and Technology, Tangshan, 063000, China.
authors.forename: Yue-Hong
authors.initials: YH
authors.lastname: Long
authors.affiliation: School of Life Sciences and Technology, Department of Breast Surgery of Yangpu Hospital, Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200092, China.
authors.forename: Su
authors.initials: S
authors.lastname: Chen
authors.affiliation: Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D020880:Neuregulins / Q000235:genetics* / Q000378:metabolism; D019899:Paracrine Communication / Q000235:genetics*; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D000092468:Bromodomain Containing Proteins
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000068818:Cetuximab; D005998:Glycine; D020880:Neuregulins; D016283:Proto-Oncogene Proteins p21(ras); D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins; C117307:KRAS protein, human; C486357:NRG3 protein, human
keywords: NRG3; RAS; WSTF; paracrine signaling