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Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells
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 the...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673252/ https://www.ncbi.nlm.nih.gov/pubmed/26035354 |
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author | Lakshmanan, Imayavaramban Seshacharyulu, Parthasarathy Haridas, Dhanya Rachagani, Satyanarayana Gupta, Suprit Joshi, Suhasini Guda, Chittibabu Yan, Ying Jain, Maneesh Ganti, Apar K. Ponnusamy, Moorthy P. Batra, Surinder K. |
author_facet | Lakshmanan, Imayavaramban Seshacharyulu, Parthasarathy Haridas, Dhanya Rachagani, Satyanarayana Gupta, Suprit Joshi, Suhasini Guda, Chittibabu Yan, Ying Jain, Maneesh Ganti, Apar K. Ponnusamy, Moorthy P. Batra, Surinder K. |
author_sort | Lakshmanan, Imayavaramban |
collection | PubMed |
description | 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; Kras(G12D); Trp53(R172H/+); 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. |
format | Online Article Text |
id | pubmed-4673252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46732522015-12-22 Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells Lakshmanan, Imayavaramban Seshacharyulu, Parthasarathy Haridas, Dhanya Rachagani, Satyanarayana Gupta, Suprit Joshi, Suhasini Guda, Chittibabu Yan, Ying Jain, Maneesh Ganti, Apar K. Ponnusamy, Moorthy P. Batra, Surinder K. Oncotarget Research Paper 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; Kras(G12D); Trp53(R172H/+); 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. Impact Journals LLC 2015-05-16 /pmc/articles/PMC4673252/ /pubmed/26035354 Text en Copyright: © 2015 Lakshmanan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Lakshmanan, Imayavaramban Seshacharyulu, Parthasarathy Haridas, Dhanya Rachagani, Satyanarayana Gupta, Suprit Joshi, Suhasini Guda, Chittibabu Yan, Ying Jain, Maneesh Ganti, Apar K. Ponnusamy, Moorthy P. Batra, Surinder K. Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title | Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title_full | Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title_fullStr | Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title_full_unstemmed | Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title_short | Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
title_sort | novel her3/muc4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673252/ https://www.ncbi.nlm.nih.gov/pubmed/26035354 |
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