title: Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells.
abstract: Several studies have demonstrated that MUC4 is involved in progression and metastasis of pancreatic cancer (PC). Here, we report that HER3/MUC4 interaction in HER2 low cells is critical in driving pancreatic tumorigenesis. Upon HER2 knockdown, we observed elevated expression of HER3 and MUC4 and their interactions, which was confirmed by immunoprecipitation and bioinformatics analyses. In paired human PC tissues, higher percentage of HER3 positivity (10/33, 30.3%; p = 0.001) was observed than HER2 (5/33, 15.1%; p = 0.031), which was further confirmed in spontaneous mice (KPC; KrasG12D; Trp53R172H/+; Pdx-Cre) tumors of different weeks. Mechanistically, increased phosphorylation of ERK and expression of PI3K and c-Myc were observed in HER2 knockdown cells, suggesting a positive role for HER3/MUC4 in HER2 low cells. Further, HER2 knockdown resulted in increased proliferation, motility and tumorigenicity of PC cells. Consistently, transient knockdown of HER3 by siRNA in HER2 knockdown cells led to decreased proliferation. These observations led us to conclude that HER3 interacts with MUC4 to promote proliferation in HER2 low PC cells. Further, deficiency of both HER2 and HER3 leads to decreased proliferation of PC cells. Hence targeting these newly identified HER3/MUC4 signals would improve the PC patients survival by intercepting MUC4 mediated oncogenic signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Imayavaramban
authors.initials: I
authors.lastname: Lakshmanan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Seshacharyulu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Haridas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Suprit
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Chittibabu
authors.initials: C
authors.lastname: Guda
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.|Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE, USA.|Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Apar K
authors.initials: AK
authors.lastname: Ganti
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.|Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Moorthy P
authors.initials: MP
authors.lastname: Ponnusamy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.|Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis; D002453:Cell Cycle; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D055264:Mucin-4 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D055264:Mucin-4; D019869:Phosphatidylinositol 3-Kinases; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C524658:MUC4 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: HER2; HER3; KPC model; MUC4; pancreatic cancer