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
Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
Cancers (Basel). 2023 Jan 31;15(3):905. doi: 10.3390/cancers15030905.
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 induction that were abolished by deleting either or . 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 or . Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the -low/-high subgroup displayed increased 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 -low/-high HCC cases.
SOCS1缺陷会增加肝细胞癌（HCC）的易感性，并促进肝脏中CDKN1A的表达。在许多癌症中，高CDKN1A表达与疾病严重程度相关。在此，我们证明了CDKN1A在二乙基亚硝胺（DEN）诱导的SOCS1缺陷小鼠肝癌中起关键致病作用。对DEN诱导的基因毒性反应的机制研究表明，SOCS1缺陷的肝细胞会上调SOCS3表达，SOCS3促进p53激活，并且通过删除 或 均可消除这种诱导。先前的报道表明CDKN1A参与促进由NRF2介导的氧化应激反应，而NRF2是DEN诱导肝癌发生所必需的。我们发现，DEN处理后，SOCS1缺陷肝脏中NRF2及其靶基因的诱导增加，而通过删除 或 可消除这种增加。SOCS1缺陷小鼠中SOCS3的缺失减少了DEN诱导的HCC的生长，但不影响肿瘤发生率。在TCGA-LIHC数据集中， -低/-高亚组显示 表达增加、NRF2转录特征富集、疾病进展更快且预后不良。总体而言，我们的研究结果表明，肝细胞中的SOCS1缺陷会促进代偿性SOCS3表达、p53激活、CDKN1A诱导和NRF2激活，这可促进细胞对氧化应激的适应并促进肿瘤生长。因此，NRF2途径代表了 -低/-高HCC病例中的潜在治疗靶点。
