PMID- 24561527
OWN - NLM
STAT- MEDLINE
DCOM- 20150408
LR  - 20220331
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 4
DP  - 2015 Jan 22
TI  - Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates 
      pancreatic tumorigenesis.
PG  - 455-64
LID - 10.1038/onc.2013.576 [doi]
AB  - Pancreatic ductal adenocarcinoma (PDAC) is the eighth largest cause of 
      cancer-related mortality across the world, with a median 5-year survival rate of 
      less than 3.5%. This is partly because the molecules and the molecular mechanisms 
      that contribute to PDAC are not well understood. Our goal is to understand the 
      role of p21-activated kinase 1 (Pak1) signaling axis in the progression of PDAC. 
      Pak1, a serine/threonine kinase, is a well-known regulator of cytoskeletal 
      remodeling, cell motility, cell proliferation and cell survival. Recent reports 
      suggest that Pak1 by itself can have an oncogenic role in a wide variety of 
      cancers. In this study, we analyzed the expression of Pak1 in human pancreatic 
      cancer tissues and found that Pak1 levels are significantly upregulated in PDAC 
      samples as compared with adjacent normals. Further, to study the functional role 
      of Pak1 in pancreatic cancer model systems, we developed stable overexpression 
      and lentiviral short hairpin RNA-mediated knockdown (KD) clones of Pak1 and 
      studied the changes in transforming properties of the cells. We also observed 
      that Pak1 KD clones failed to form tumors in nude mice. By adopting a 
      quantitative PCR array-based approach, we identified fibronectin, a component of 
      the extracellular matrix and a mesenchymal marker, as a transcriptional target of 
      Pak1 signaling. The underlying molecular mechanism of Pak1-mediated 
      transformation includes its nuclear import and recruitment to the fibronectin 
      promoter via interaction with nuclear factor-kappaB (NF-kappaB)-p65 complex. To our 
      knowledge, this is the first study illustrating Pak1-NF-kappaB-p65-mediated 
      fibronectin regulation as a potent tumor-promoting mechanism in KRAS intact 
      model.
FAU - Jagadeeshan, S
AU  - Jagadeeshan S
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Krishnamoorthy, Y R
AU  - Krishnamoorthy YR
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Singhal, M
AU  - Singhal M
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Subramanian, A
AU  - Subramanian A
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Mavuluri, J
AU  - Mavuluri J
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Lakshmi, A
AU  - Lakshmi A
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Roshini, A
AU  - Roshini A
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
FAU - Baskar, G
AU  - Baskar G
AD  - Department of Human Genetics, Sri Ramachandra University, Chennai, India.
FAU - Ravi, M
AU  - Ravi M
AD  - Department of Human Genetics, Sri Ramachandra University, Chennai, India.
FAU - Joseph, L D
AU  - Joseph LD
AD  - Department of Pathology, Sri Ramachandra University, Chennai, India.
FAU - Sadasivan, K
AU  - Sadasivan K
AD  - Department of Plastic and Reconstructive Surgery, Government Medical College, 
      Thiruvananthapuram, India.
FAU - Krishnan, A
AU  - Krishnan A
AD  - Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
FAU - Nair, A S
AU  - Nair AS
AD  - Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
FAU - Venkatraman, G
AU  - Venkatraman G
AD  - Department of Human Genetics, Sri Ramachandra University, Chennai, India.
FAU - Rayala, S K
AU  - Rayala SK
AD  - Department of Biotechnology, Indian Institute of Technology Madras (IITM), 
      Chennai, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140224
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Fibronectins)
RN  - 0 (Transcription Factor RelA)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
SB  - IM
MH  - Animals
MH  - Carcinoma, Pancreatic Ductal/*etiology/metabolism
MH  - Cell Line, Tumor
MH  - *Cell Transformation, Neoplastic
MH  - Fibronectins/*genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Mice
MH  - Pancreatic Neoplasms/*etiology/metabolism
MH  - Promoter Regions, Genetic
MH  - Transcription Factor RelA/physiology
MH  - *Transcription, Genetic
MH  - p21-Activated Kinases/*physiology
EDAT- 2014/02/25 06:00
MHDA- 2015/04/09 06:00
CRDT- 2014/02/25 06:00
PHST- 2013/06/10 00:00 [received]
PHST- 2013/12/03 00:00 [revised]
PHST- 2013/12/07 00:00 [accepted]
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2015/04/09 06:00 [medline]
AID - onc2013576 [pii]
AID - 10.1038/onc.2013.576 [doi]
PST - ppublish
SO  - Oncogene. 2015 Jan 22;34(4):455-64. doi: 10.1038/onc.2013.576. Epub 2014 Feb 24.