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TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway
Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential r...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260882/ https://www.ncbi.nlm.nih.gov/pubmed/34249724 http://dx.doi.org/10.3389/fonc.2021.680985 |
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author | Feng, Fang Liu, Chunliang Bian, Huahui Cai, Wei Zhou, Ying Zhou, Li Zhuang, Zhixiang |
author_facet | Feng, Fang Liu, Chunliang Bian, Huahui Cai, Wei Zhou, Ying Zhou, Li Zhuang, Zhixiang |
author_sort | Feng, Fang |
collection | PubMed |
description | Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer. |
format | Online Article Text |
id | pubmed-8260882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82608822021-07-08 TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway Feng, Fang Liu, Chunliang Bian, Huahui Cai, Wei Zhou, Ying Zhou, Li Zhuang, Zhixiang Front Oncol Oncology Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer. Frontiers Media S.A. 2021-06-23 /pmc/articles/PMC8260882/ /pubmed/34249724 http://dx.doi.org/10.3389/fonc.2021.680985 Text en Copyright © 2021 Feng, Liu, Bian, Cai, Zhou, Zhou and Zhuang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Feng, Fang Liu, Chunliang Bian, Huahui Cai, Wei Zhou, Ying Zhou, Li Zhuang, Zhixiang TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title | TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title_full | TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title_fullStr | TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title_full_unstemmed | TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title_short | TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway |
title_sort | tipe2 suppresses malignancy of pancreatic cancer through inhibiting tgfβ1 mediated signaling pathway |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260882/ https://www.ncbi.nlm.nih.gov/pubmed/34249724 http://dx.doi.org/10.3389/fonc.2021.680985 |
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