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KMT2D links TGF-ß signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.
Lu, Shuang; Kim, Hong Sun; Cao, Yubo; Bedi, Karan; Zhao, Lili; Narayanan, Ishwarya Venkata; Magnuson, Brian; Gu, Yumei; Yang, Jing; Yi, Zhujun; Babaniamansour, Sepideh; Shameon, Sargis; Xu, Chang; Paulsen, Michelle T; Qiu, Ping; Jeyarajan, Sivakumar; Ljungman, Mats; Thomas, Dafydd; Dou, Yali; Crawford, Howard; di Magliano, Marina Pasca; Ge, Kai; Yang, Bo; Shi, Jiaqi.
Afiliação
  • Lu S; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Kim HS; Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  • Cao Y; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Bedi K; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Zhao L; Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Narayanan IV; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Magnuson B; Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Gu Y; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Yang J; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Yi Z; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Babaniamansour S; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Shameon S; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Xu C; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Paulsen MT; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Qiu P; Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Jeyarajan S; Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Ljungman M; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Thomas D; Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Dou Y; Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Crawford H; Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • di Magliano MP; Henry Ford Pancreatic Cancer Center, Detroit, Michigan, USA.
  • Ge K; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Yang B; National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, USA.
  • Shi J; Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Int J Cancer ; 153(3): 552-570, 2023 Aug 01.
Article em En | MEDLINE | ID: mdl-37140208
ABSTRACT
Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-ß to the activin A pathway. We found that TGF-ß upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / MicroRNAs Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / MicroRNAs Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos