FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY

FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY

Bibliographic Details
Main Author: Liu, Xin
Language:English
Published: The Ohio State University / OhioLINK 2016
Subjects:
Cellular Biology
Molecular Biology
pancreatic cancer
Hedgehog Signaling
PTEN
Autophagy
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1479576092637914
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1479576092637914
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Cellular Biology
Molecular Biology
pancreatic cancer
Hedgehog Signaling
PTEN
Autophagy
spellingShingle Cellular Biology
Molecular Biology
pancreatic cancer
Hedgehog Signaling
PTEN
Autophagy
Liu, Xin
FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
author Liu, Xin
author_facet Liu, Xin
author_sort Liu, Xin
title FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
title_short FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
title_full FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
title_fullStr FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
title_full_unstemmed FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY
title_sort function of pten in stromal fibroblasts in regulating pacreatic tumorigenesis and in regulating autophagy
publisher The Ohio State University / OhioLINK
publishDate 2016
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1479576092637914
work_keys_str_mv AT liuxin functionofpteninstromalfibroblastsinregulatingpacreatictumorigenesisandinregulatingautophagy
_version_ 1723964831976914944
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu14795760926379142021-12-19T05:38:18Z FUNCTION OF PTEN IN STROMAL FIBROBLASTS IN REGULATING PACREATIC TUMORIGENESIS AND IN REGULATING AUTOPHAGY Liu, Xin Cellular Biology Molecular Biology pancreatic cancer Hedgehog Signaling PTEN Autophagy Pancreatic cancer, commonly referred to as pancreatic ductal adenocarcinoma (PDAC), ranks number four in cancer related death in the western world. Despite the advances in treatment of many other types of cancer, the prognosis of PDA remains poor. The heterogeneity of pancreatic cancer hindered our understanding of the mechanisms of this disease. A hallmark of pancreatic cancer is the desmoplastic tumor stroma that arises in response to tumor progression. Activated fibroblasts (often termed stellate cells) are a major component of this stroma. Both oncogenic and suppressive roles of stromal fibroblasts have been reported to contribute to pancreatic tumor progression. However, the role of microenvironment during the acinar-ductal metaplasia (ADM), an early stage of pancreatic cancer, remains unclear.In the present study, we examined paracrine Hedgehog signaling in stromal fibroblasts in a Kras-initiated pancreatic ADM mouse model. We demonstrated that ablation of the Smoothened (Smo) gene in fibroblasts lead to increased ADM and enhanced the growth and proliferation of pancreatic tumor cell lines in vivo. Moreover we demonstrated Smo ablation lead to activation of oncogenic PI3K-AKT signaling, which upregulated GLI2-mediated TGFa production in fibroblasts and subsequent EGFR activation in the epithelium. Thus, crosstalk between Hedgehog/SMO and AKT/GLI2 pathways is a mechanism that converts tumor-suppressive fibroblasts into tumor-promoting fibroblasts.Further analysis showed re-activation PI3K/AKT pathway in SMO-deleted fibroblast compartment: the crucial role of tumor suppressor PTEN. PTEN was degraded in a proteasome-dependent manner in SMO-deleted fibroblasts, and an unbiased screen of the PTEN interactome revealed RNF5 as a novel E3 ubiquitin ligase for PTEN. RNF5 was shown to directly interact with and facilitate ubiquitin transfer to PTEN, and over-expression of RNF5 led to PTEN degradation. Knockdown of RNF5, in the context of SMO deletion, restored PTEN levels to normal. In addition, PTEN was marked for RNF5-mediated degradation by GSK3ß phosphorylation, and pharmacological inhibition of GSK rescued PTEN levels. Loss of PTEN in the fibroblast compartment was sufficient to accelerate tumor growth and proliferation in vivo. Loss of fibroblast PTEN also led to increased angiogenesis in tumors and decreased hydraulic permeability in vitro. Furthermore, low stromal PTEN expression, measured in PDAC patient samples, correlated with low SMO expression and reduced overall survival. These results define a tumor-suppressing role of PTEN when hedgehog signaling is disrupted in stromal fibroblasts. Lastly, by analyzing the PTEN interactome proteomic array data, we identified a novel role of PTEN in regulating autophagy via its protein phosphatase activity. Previous reports suggested PTEN can induce autophagy by inhibiting PI3K–AKT–mTOR pathway via its lipid phosphatase activity. However in our study, we found that PTEN can directly regulate ATG4B activity and affect the autophagy activity. This new function of PTEN relies on its protein phosphatase activity. PTEN knockout mouse embryonic fibroblasts (MEFs) showed aberrant LC3 maturation and processing compared to the wildtype. ATG4B enzymatic activity from wildtype MEFs behaved like PTENG129E mutant (no lipid phosphatase activity but with protein phosphatase activity) cells while ATG4B activity from PTEN knockout MEFs like PTENC124S mutants (no lipid and protein phosphatase activity). Incubation with the recombinant PTEN protein can decrease ATG4B activity. More evidence is needed to validate if PTEN is a direct phosphatase of ATG4B and be able to regulate its hydrolase activity. Taken together, we have identified an essential role of PTEN in regulating pancreatic tumorigenesis and progression from hedgehog mediated stromal fibroblasts and discovered its novel role in regulating autophagy. 2016 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1479576092637914 http://rave.ohiolink.edu/etdc/view?acc_num=osu1479576092637914 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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