Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells
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Imayavaramban Lakshmanan1, Parthasarathy Seshacharyulu1, Dhanya Haridas1, Satyanarayana Rachagani1, Suprit Gupta1, Suhasini Joshi1, Chittibabu Guda2, Ying Yan3, Maneesh Jain1,6, Apar K. Ganti4,5, Moorthy P. Ponnusamy1,6, Surinder K. Batra1,6
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
3Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
4Department of Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE, USA
5Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
6Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Surinder K. Batra, e-mail: [email protected]
Moorthy P. Ponnusamy, e-mail: [email protected]
Keywords: pancreatic cancer, HER2, HER3, MUC4, KPC model
Received: February 02, 2015 Accepted: May 05, 2015 Published: May 16, 2015
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.
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