p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma

Luo, Yichen; Fang, Lei; Yu, Hongqiang; Zhang, Jie; Lin, Xiaotong; Liu, Xiaoyu; Wu, Di; Li, Gui-Xi; Deng, Hongkuan; Zhang, Yujun; Chen, Shu; Jiang, Yan; Shuai, Ling; He, Yu; Zhang, Lei-Da; Bie, Ping; Xie, Chuan‐Ming

doi:10.1016/j.jhep.2020.07.036

Cited by 59 publications

(40 citation statements)

References 50 publications

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“…By combining Gene Ontology (GO) terms, KEGG and Wiki pathways, ClueGo/CluePedia create a better interpretation of the pathways associated with the list of input genes [29] . Hypoxia mimicking conditions in group 2 induced cellular responses to hypoxia and HIF-1 signaling pathway, as well as other signaling pathways reported to promote HCC including NRF2, FOXO, and p53 pathways [30,31] (Fig. 3A-B).…”

Section: Differential Gene Expression Analysismentioning

confidence: 87%

Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool

Hrout

Cervantes-Gracia

Chahwan

et al. 2021

Preprint

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The tumor microenvironment and its contribution to tumorigenesis has been a focal highlight in recent years. A two-way communication between the tumor and the surrounding microenvironment sustains and contributes to the growth and metastasis of tumors. Progression and metastasis of hepatocellular carcinoma have been reported to be exceedingly influenced by diverse microenvironmental cues. In this study, we present a 3D-culture model of liver cancer to better mimic in vivo tumor settings. By creating novel 3D co-culture model that combines free-floating and scaffold based 3D-culture techniques of liver cancer cells and fibroblasts, we aimed to establish a simple albeit reproducible ex vivo cancer microenvironment model that captures tumor-stroma interactions. The model presented herein exhibited unique gene expression and protein expression profiles when compared to 2D and 3D mono-cultures of liver cancer cells. Our results showed that in vivo like conditions cannot be mimicked by simply growing cancer cells as spheroids, but by co-culturing them with 3D fibroblast with which they were able to cross-talk. This was evident by the upregulation of several pathways involved in HCC, and the increase in secreted factors by co-cultured cancer cells, many of which are also involved in tumor-stroma interactions. Compared to the conventional 2D culture, the proposed model exhibits an increase in the expression of genes associated with development, progression, and poor prognosis of HCC. Our results correlated with an aggressive outcome that better mirrors in vivo HCC, and therefore, a more reliable platform for molecular understanding of HCC and possibly better anti-cancer drug screening.

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Section: Differential Gene Expression Analysismentioning

confidence: 87%

Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool

Hrout

Cervantes-Gracia

Chahwan

et al. 2021

Preprint

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“…In that study, Lu et al suggested that E6 protein binds to the tumor suppressor protein, tuberin, and causes the proteasomemediated degradation of tuberin, leading to the activation of S6 kinase downstream of the Akt signaling pathway (12). In addition, Luo et al reported that TSC1 loss facilitates the p53 haploinsufficiency-mediated activation of the Pten/PI3K/Akt/mTOR axis and its downstream target Abcc4, leading to hepatocellular carcinoma tumorigenesis and metastasis (13). Further studies need to be conducted to better elucidate the association between TSC and malignancy; however, a few studies seem to suggest that alterations in the mTOR pathway and a secondary "hit", such as TP53 mutation HPV infection, may contribute to malignancy formation.…”

Section: Discussionmentioning

confidence: 99%

Tuberous sclerosis complex misdiagnosed as multiple metastases in a cervical cancer patient: case report and literature review

Ye¹,

Feng²,

Peng³

et al. 2021

Ann Palliat Med

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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organs and is caused by inactive mutations in the TSC1 or TSC2 genes. The main symptoms of TSC are neurocutaneous syndrome and benign hamartoma formation. Notably, malignancy is not an indication of TSC. In this article, we present the case of a 48-year-old female with cervical cancer (CC) combined with TSC, who was misdiagnosed with multiple metastases. Toe masses, pelvic nodules, and multiple osteogenic lesions were initially observed. Multi-site puncture biopsies and a toe amputation were performed; the pathology results did not indicate malignancy. Subsequently, hypomelanotic macules on the back, subependymal nodules (SENs), ungual fibromas, multiple renal cysts, and sclerotic-bone-lesions (SBLs) of the skull, and vertebrae were observed, leading to a diagnosis of TSC. Given that TSC is a benign disease and has not yet caused any organ disfunction, no special treatment was provided to this patient.After a follow-up period of almost 65 months, the patient's quality of life remained good without therapy.Oncologists should pay attention to benign diseases in the face of multiple lesions to reduce misdiagnosis and overtreatment. In addition, TSC may interact with CC through molecular mechanisms, such as the mammalian target of rapamycin (mTOR) pathway.

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“…The results showed that the major functions and pathways were enriched in the P53 signalling, mTOR signalling, NOTCH signalling, cell cycle, ubiquitin-mediated proteolysis, and T cell receptor signalling pathways. Among these pathways, the P53, mTOR and NOTCH signalling pathways are correlated with HCC metastasis, which is the main reason for a poor prognosis [45,46].…”

Section: Discussionmentioning

confidence: 99%

Identification of CDC20 As an Immune Infiltration-Correlated Prognostic Biomarker in Hepatocellular Carcinoma

Xiong

Wang

et al. 2021

Preprint

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Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. Some E3 ubiquitin-protein ligases play essential roles in HCC development. We aimed to explore a hub E3 ubiquitin-protein ligase gene and verify its association with prognosis and immune cell infiltration in HCC. We identified cell division cycle 20 (CDC20) as a hub E3 ubiquitin-protein ligase in HCC by determining the intersecting genes in a protein-protein interaction (PPI) network of differentially expressed genes (DEGs) in HCC data from the International Cancer Genome Consortium (ICGC) and 919 E3 ubiquitin-protein ligase genes from the Integrated annotations for Ubiquitin and Ubiquitin-like Conjugation Database (IUUCD). DEGs and their correlations with clinicopathological features were explored in The Cancer Genome Atlas (TCGA), ICGC, and Gene Expression Omnibus (GEO) databases via the Wilcoxon signed-rank test. The prognostic value of CDC20 was illustrated by Kaplan-Meier (K-M) curves and Cox regression analyses. Subsequently, the correlation between CDC20 and immune infiltration was demonstrated via the Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). CDC20 expression was significantly higher in HCC than in normal tissues (all P < 0.05). K-M curves and Cox regression analyses showed that high CDC20 expression predicted a poor prognosis and might be an independent risk factor for HCC prognosis (P < 0.05). Additionally, the TIMER and GEPIA results indicated that CDC20 is correlated with the immune infiltration of CD8 + T cells, T cells (general), monocytes, and exhausted T cells. This research revealed the potential prognostic value of CDC20 in HCC and demonstrated that CDC20 might be an immune-associated therapeutic target in HCC because of its correlation with immune infiltration.

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p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma

Cited by 59 publications

References 50 publications

Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool

Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool

Tuberous sclerosis complex misdiagnosed as multiple metastases in a cervical cancer patient: case report and literature review

Identification of CDC20 As an Immune Infiltration-Correlated Prognostic Biomarker in Hepatocellular Carcinoma

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