E2F target score is associated with cell proliferation and survival of patients with hepatocellular carcinoma

Chida, Kohei; Oshi, Masanori; Roy, Arya Mariam; Yachi, Takafumi; Nara, Masaki; Yamada, Kyogo; Matsuura, Osamu; Hashizume, T; Endo, Itaru; Takabe, Kazuaki

doi:10.1016/j.surg.2023.04.030

Cited by 6 publications

(2 citation statements)

References 41 publications

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“…These cell proliferation-related and cell-cycle gene pathways genes have an important role in the pathogenesis of HCC. Our previous study showed that upregulation of individual E2F targets was associated with worse OS and DFS in HCC, especially the alterations in E2F3, E2F5 and E2F6 [ 73 ]. Furthermore, a metanalysis of c-Myc overexpression in HCC was associated with worse oncologic outcomes [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

High Ki67 Gene Expression Is Associated With Aggressive Phenotype in Hepatocellular Carcinoma

Ramos-Santillan,

Oshi,

Nelson

et al. 2024

World J Oncol

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Background Hepatocellular carcinoma (HCC) with high Ki67 protein expression, the most commonly used cell proliferation marker, is associated with an aggressive biologic phenotype; however, conventional immunostaining is hampered by variability in institutional protocol, specific antibody probe, and by assessor subjectivity. To this end, we hypothesized that Ki67 gene ( MKi67 ) expression would identify highly proliferative HCC, and clarify its association with oncologic outcome, tumor progression, and immune cell population in the tumor microenvironment (TME). Furthermore, we sought to identify the cell-cycle gene expression profile that confers this aggressive phenotype. Methods A total of 473 HCC patients with clinicopathological data associated with transcriptome were selected for this study: 358 patients from The Cancer Genome Atlas (TCGA) as the testing cohort, and 115 from GSE76427 as the validation cohort. Each cohort was divided into a highly proliferative group (MKi67-high) and the low MKi67 group (MKi67-low) by the median of Ki67 gene ( MKi67 ) expression levels. Results MKi67-high HCC patients had worse disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) independent of histological grade in the TCGA cohort. MKi67 expression correlated with histological grade and tumor size. MKi67 expression increased throughout the HCC carcinomatous sequence from normal liver, cirrhotic liver, early HCC, and advanced HCC. MKi67-high HCC was associated with higher intratumor heterogeneity, homologous recombination deficiency, and altered fraction as well as intratumoral infiltration of T helper type 1 (Th1) and Th2 cells, but lower interferon-gamma response and M2 macrophage infiltration. Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, Myc target v1 and mitotic spindle), MTORC1 signaling, DNA repair, PI3K MTOR signaling, and unfolded protein response were all enriched in the MKi67-high HCC (false discovery rate (FDR) < 0.25). Conclusions High MKi67 gene expression identified highly proliferative HCC with aggressive biology involving classical pathways in cell cycle regulation and DNA repair, as well as poor overall oncologic outcomes. This suggests potential for personalized treatment strategies, but validation and refinement of these observations require further research to elucidate the underlying mechanisms and validate therapeutic targeting of these pathways in MKi67-high HCC tumors.

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Section: Discussionmentioning

confidence: 99%

High Ki67 Gene Expression Is Associated With Aggressive Phenotype in Hepatocellular Carcinoma

Ramos-Santillan,

Oshi,

Nelson

et al. 2024

World J Oncol

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“…Previously, we utilized gene set variation analysis (GSVA) on the transcriptome of bulk tumors to explore the impact of signaling networks in various malignancy types including HCC [9][10][11]. GSVA scores, estimating pathway activation levels by analyzing numerous genes associated with a given pathway [12], were calculated.…”

Section: Introductionmentioning

confidence: 99%

Higher Inflammatory Response in Hepatocellular Carcinoma is Associated with Immune Cell Infiltration and a Better Outcome

Oshi,

Chida,

Roy

et al. 2024

Preprint

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Background & Aims: Hepatocellular carcinoma (HCC) often develops from chronic liver inflammation. Inflammation within a tumor can either promote cancer progression or activate an immune response against it. This study aims to determine the clinical significance of enhanced inflammation in HCC. Methods: Data from 655 HCC patients across four cohorts (TCGA, GSE6764, GSE76427, GSE89377) were examined. Inflammatory response was quantified using a scoring system derived from the gene set variation analysis of the “INFLAMMATORY_RESPONSE” gene set. Results: A stepwise increase in inflammatory response was noted from normal liver to cirrhosis, with consistently lower levels in HCC across both GSE6764 and GSE89377 cohorts (both p<0.001). Similar trends were observed in interferon response, pathways such as IL6/JAK/STAT3 and complement signaling, coagulation cascade, and allograft rejection (all p<0.02). HCCs with high inflammatory response were associated with increased immune cell infiltrations (p<0.01) and cytolytic activity (p<0.001). Interestingly, these HCCs had reduced mutation rates, no relationship with cell proliferation, and displayed both immune responses and pro-cancerous signals including epithelial-mesenchymal transition, KRAS, and hypoxia. Further, a high inflammatory score correlated with improved disease-free survival in TCGA (p=0.034) and overall survival in GSE76427 (p=0.008). Conclusion: HCC with higher levels of inflammatory response demonstrated increased immune cell infiltration, enhanced immune-related and other pro-cancerous-related signaling, and better patient prognosis.

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Higher inflammatory response in hepatocellular carcinoma is associated with immune cell infiltration and a better outcome

Oshi,

Chida,

Roy

et al. 2024

Hepatol Int

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E2F target score is associated with cell proliferation and survival of patients with hepatocellular carcinoma

Cited by 6 publications

References 41 publications

High Ki67 Gene Expression Is Associated With Aggressive Phenotype in Hepatocellular Carcinoma

High Ki67 Gene Expression Is Associated With Aggressive Phenotype in Hepatocellular Carcinoma

Higher Inflammatory Response in Hepatocellular Carcinoma is Associated with Immune Cell Infiltration and a Better Outcome

Higher inflammatory response in hepatocellular carcinoma is associated with immune cell infiltration and a better outcome

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