Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673252/
https://www.ncbi.nlm.nih.gov/pubmed/26035354
_version_ 1782404700769878016
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
work_keys_str_mv AT lakshmananimayavaramban novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT seshacharyuluparthasarathy novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT haridasdhanya novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT rachaganisatyanarayana novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT guptasuprit novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT joshisuhasini novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT gudachittibabu novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT yanying novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT jainmaneesh novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT gantiapark novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT ponnusamymoorthyp novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells
AT batrasurinderk novelher3muc4oncogenicsignalingaggravatesthetumorigenicphenotypesofpancreaticcancercells