Cargando…
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation
SIMPLE SUMMARY: Gene coding for the SOCS1 protein is frequently inactivated in liver cancer, suggesting that SOCS1 protects liver cells from becoming cancerous. This notion is supported by the increased susceptibility of mice lacking SOCS1 to develop liver cancer. Understanding how the SOCS1 protein...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913612/ https://www.ncbi.nlm.nih.gov/pubmed/36765862 http://dx.doi.org/10.3390/cancers15030905 |
_version_ | 1784885469667917824 |
---|---|
author | Khan, Md Gulam Musawwir Boufaied, Nadia Yeganeh, Mehdi Kandhi, Rajani Petkiewicz, Stephanie Sharma, Ankur Yoshimura, Akihiko Ferbeyre, Gerardo Labbé, David P. Ramanathan, Sheela Ilangumaran, Subburaj |
author_facet | Khan, Md Gulam Musawwir Boufaied, Nadia Yeganeh, Mehdi Kandhi, Rajani Petkiewicz, Stephanie Sharma, Ankur Yoshimura, Akihiko Ferbeyre, Gerardo Labbé, David P. Ramanathan, Sheela Ilangumaran, Subburaj |
author_sort | Khan, Md Gulam Musawwir |
collection | PubMed |
description | SIMPLE SUMMARY: Gene coding for the SOCS1 protein is frequently inactivated in liver cancer, suggesting that SOCS1 protects liver cells from becoming cancerous. This notion is supported by the increased susceptibility of mice lacking SOCS1 to develop liver cancer. Understanding how the SOCS1 protein protects from liver cancer could help in the development of new treatment strategies. CDKN1A is another protein that protects against many cancers including liver cancer. However, under certain unknown circumstances, CDKN1A can play a completely opposite role in promoting cancer growth. When CDKN1A gains such an undesirable function is not clear. Our findings on mouse models of liver cancer, and data from human liver cancer patients, show that SOCS1 suppresses the expression of CDKN1A, and in doing so, prevents the ability of liver cells to withstand the stress associated with cancer growth. This stress reduction pathway represents a potential therapeutic target in SOCS1-less liver cancers. ABSTRACT: SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases. |
format | Online Article Text |
id | pubmed-9913612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99136122023-02-11 SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation Khan, Md Gulam Musawwir Boufaied, Nadia Yeganeh, Mehdi Kandhi, Rajani Petkiewicz, Stephanie Sharma, Ankur Yoshimura, Akihiko Ferbeyre, Gerardo Labbé, David P. Ramanathan, Sheela Ilangumaran, Subburaj Cancers (Basel) Article SIMPLE SUMMARY: Gene coding for the SOCS1 protein is frequently inactivated in liver cancer, suggesting that SOCS1 protects liver cells from becoming cancerous. This notion is supported by the increased susceptibility of mice lacking SOCS1 to develop liver cancer. Understanding how the SOCS1 protein protects from liver cancer could help in the development of new treatment strategies. CDKN1A is another protein that protects against many cancers including liver cancer. However, under certain unknown circumstances, CDKN1A can play a completely opposite role in promoting cancer growth. When CDKN1A gains such an undesirable function is not clear. Our findings on mouse models of liver cancer, and data from human liver cancer patients, show that SOCS1 suppresses the expression of CDKN1A, and in doing so, prevents the ability of liver cells to withstand the stress associated with cancer growth. This stress reduction pathway represents a potential therapeutic target in SOCS1-less liver cancers. ABSTRACT: SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases. MDPI 2023-01-31 /pmc/articles/PMC9913612/ /pubmed/36765862 http://dx.doi.org/10.3390/cancers15030905 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Khan, Md Gulam Musawwir Boufaied, Nadia Yeganeh, Mehdi Kandhi, Rajani Petkiewicz, Stephanie Sharma, Ankur Yoshimura, Akihiko Ferbeyre, Gerardo Labbé, David P. Ramanathan, Sheela Ilangumaran, Subburaj SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title | SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title_full | SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title_fullStr | SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title_full_unstemmed | SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title_short | SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation |
title_sort | socs1 deficiency promotes hepatocellular carcinoma via socs3-dependent cdkn1a induction and nrf2 activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913612/ https://www.ncbi.nlm.nih.gov/pubmed/36765862 http://dx.doi.org/10.3390/cancers15030905 |
work_keys_str_mv | AT khanmdgulammusawwir socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT boufaiednadia socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT yeganehmehdi socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT kandhirajani socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT petkiewiczstephanie socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT sharmaankur socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT yoshimuraakihiko socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT ferbeyregerardo socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT labbedavidp socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT ramanathansheela socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation AT ilangumaransubburaj socs1deficiencypromoteshepatocellularcarcinomaviasocs3dependentcdkn1ainductionandnrf2activation |