• apoptosis
• autophagy
• cell death
• drug repurposing
• hepatocellular carcinoma
• metformin
• sorafenib
• valproic acid

• Humans
• Carcinoma, Hepatocellular/metabolism
• Sorafenib/pharmacology
• Sorafenib/therapeutic use
• Liver Neoplasms/metabolism
• Valproic Acid/pharmacology
• Valproic Acid/therapeutic use
• Bevacizumab
• Metformin/pharmacology
• Metformin/therapeutic use
• Cell Death

• 2023-3-135 Mexican Social Security Institute

• E2F transcription factor 1
• hepatocellular carcinoma
• tissue microarray

• Humans
• Carcinoma, Hepatocellular/pathology
• Cell Cycle
• E2F1 Transcription Factor/genetics
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms/pathology
• Prognosis

• E2F target
• drug sensitivity
• hepatocellular carcinoma
• immune landscape
• prognosis

• Bioinformatic analysis
• Hepatocellular carcinoma
• Prognosis
• Small nucleolar RNA host gene 4

We planned to uncover the cancer stemness-related genes (SRGs) in prostate cancer (PCa) and its underlying mechanism in PCa metastasis.

We acquired the RNA-seq data of 406 patients with PCa from the TCGA database. Based on the mRNA stemness index (mRNAsi) calculated by one-class logistic regression (OCLR) algorithm, SRGs in PCa were extracted by WGCNA. Univariate and multivariate regression analyses were applied to uncover OS-associated SRGs. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Pearson's correlation analysis were performed to discover the possible mechanism of PCa metastasis. The significantly correlated transcription factors of OS-associated SRGs were also identified by Pearson's correlation analysis. ChIP-seq was applied to validate the binding relationship of TFs and OS-associated SRGs and spatial transcriptome and single-cell sequencing were performed to uncover the location of key biomarkers expression. Lastly, we explored the specific inhibitors for SRGs using CMap algorithm.

We identified 538 differentially expressed genes (DEGs) between non-metastatic and metastatic PCa. Furthermore, OS-associated SRGs were identified. The Pearson correlation analysis revealed that FOXM1 was significantly correlated with NEIL3 (correlation efficient =0.89, p < 0.001) and identified hallmark_E2F_targets as the potential pathway mechanism of NEIL3 promoting PCa metastasis (correlation efficient =0.58, p < 0.001). Single-cell sequencing results indicated that FOXM1 regulating NEIL3 may get involved in the antiandrogen resistance of PCa. Rottlerin was discovered to be a potential target drug for PCa.

We constructed a regulatory network based on SRGs associated with PCa metastasis and explored possible mechanism.

To determine the regulatory role of E2F1 in maintaining gastric cancer stemness properties and the clinical significance of E2F1 in gastric cancer.

We conducted a tumor spheroid formation assay to enrich gastric cancer stem-like cells. The protein and mRNA expression levels of genes were measured using Western Blot and qRT-PCR. Lentivirus-mediated overexpression and downregulation of E2F1 were performed to evaluate the effect of E2F1 on the stemness properties of gastric cancer cells. The effect of E2F1 on gastric cancer cell sensitivity of 5-Fu was evaluated using cell viability assay and TdT-mediated dUTP Nick-End Labeling staining. We also analyzed the association between E2F1 expression and clinical characteristics in gastric cancer patients. The KM plotter database was used to analyze the relationship between E2F1 and overall survival in GC patients.

We found that E2F1 expression was significantly higher in gastric cancer tissues than in the paired adjacent normal tissues (p < 0.05) and was positively correlated with tumor size (p < 0.05), T stage (p < 0.05), and differentiation degree (p < 0.05). KM plotter database demonstrated a close association between higher E2F1 expression level and worse overall survival of gastric cancer patients (p < 0.05). In vitro assay illustrated that E2F1 could regulate the expression of stemness-associated genes, such as BMI1, OCT4, Nanog, and CD44, and maintain the tumor spheroid formation ability of gastric cancer cells. E2F1 enhanced 5-Fu resistance in gastric cancer cells, and the E2F1 expression level was correlated with the prognosis of gastric cancer patients receiving 5-Fu therapy. The expression levels of stemness-associated genes were also significantly higher in gastric cancer tissues than the paired adjacent normal tissues (p < 0.05). A positive correlation was observed between E2F1 and BMI1 (r = 0.422, p < 0.05), CD44 (r = 0.634, p < 0.05), OCT4 (r = 0.456, p < 0.05), and Nanog (r = 0.337, p < 0.05) in gastric cancer tissues. The co-overexpression of E2F1 and stemness-associated genes was associated with worse overall survival.

E2F1 plays a significant role in gastric cancer progression by maintaining gastric cancer stemness properties through the regulation of stemness-associated genes. The close association between E2F1 and poor prognosis of patients suggests that E2F1 could serve as a prognostic biomarker and a therapeutic target in gastric cancer patients.

PIN1 is a peptidyl-prolyl cis/trans isomerase that specifically binds and catalyzes the cis/trans isomerization of the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its interacting proteins. Through this phosphorylation-dependent prolyl isomerization, PIN1 is involved in the regulation of various important cellular processes including cell cycle progression, cell proliferation, apoptosis and microRNAs biogenesis; hence its dysregulation contributes to malignant transformation. PIN1 is highly expressed in hepatocellular carcinoma (HCC). By fine-tuning the functions of its interacting proteins such as cyclin D1, x-protein of hepatitis B virus and exportin 5, PIN1 plays an important role in hepatocarcinogenesis. Growing evidence supports that targeting PIN1 is a potential therapeutic approach for HCC by inhibiting cell proliferation, inducing cellular apoptosis, and restoring microRNAs biogenesis. Novel formulation of PIN1 inhibitors that increases in vivo bioavailability of PIN1 inhibitors represents a promising future direction for the therapeutic strategy of HCC treatment. In this review, the mechanisms underlying PIN1 over-expression in HCC are explored. Furthermore, we also discuss the roles of PIN1 in HCC tumorigenesis and metastasis through its interaction with various phosphoproteins. Finally, recent progress in the therapeutic options targeting PIN1 for HCC treatment is examined and summarized.

• PIN1
• hepatocarcinogenesis
• hepatocellular carcinoma
• inhibitor
• phosphorylation

• Hepatocellular carcinoma
• Plasminogen activator inhibitor 2
• Prognosis
• RB/E2F1
• Urokinase-type plasminogen activator

E2Fs, as a family of pivotal transcription factors, have been implicated in multiple biological functions in human cancer; however, the expression and prognostic significance of E2Fs in breast cancer remains unknown. In the present study, the mRNA expression patterns of E2Fs in breast cancer were investigated with Oncomine and The Cancer Genome Atlas data. Prognostic values of E2Fs for patients with breast cancer were determined using the Kaplan-Meier plotter database. The results strongly indicated that E2F1, E2F2, E2F3, E2F5, E2F7 and E2F8 were overexpressed in patients with breast cancer, whereas E2F4 and E2F6 exhibited no expression difference between patients with cancer and healthy controls. In survival analyses, elevated E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival, relapse-free survival (RFS), distant metastasis-free survival (DMFS) or post-progression survival for patients with breast cancer. Furthermore, high expression of E2F4 indicated improved RFS but reduced DMFS. Subgroup analyses based on four clinicopathological factors further revealed that E2Fs were associated with the prognosis of patients with breast cancer in an estrogen receptor-, progesterone receptor-, human epidermal growth factor 2- and lymph node status-specific manner. These data indicated that E2Fs may serve as promising biomarkers and therapeutic targets for breast cancer.

• E2F
• Kaplan-Meier plotter
• bioinformatics
• breast cancer
• oncomine
• prognosis
• the cancer genome atlas

Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is involved in cell proliferation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms linking gene expression and tumor formation remain unclear. In this study, we found that ISX transcriptionally activated E2F transcription factor 1 (E2F1) and associated oncogenic activity by directly binding to the E2 site of its promoter. Forced expression of ISX increased the expression of and phosphorylated the serine residue at position 332 of E2F1, which may be translocated into the nucleus to form the E2F1–DP-1 complex, suggesting that the promotion of oncogenic activities of the ISX–E2F1 axis plays a critical role in hepatoma cells. Coexpression of ISX and E2F1 significantly promoted p53 and RB-mediated cell proliferation and anti-apoptosis, and repressed apoptosis and autophagy. In contrast, short hairpin RNAi-mediated attenuation of ISX and E2F1 decreased cell proliferation and malignant transformation, respectively, in hepatoma cells in vitro and in vivo. The mRNA expression of E2F1 and ISX in 238 paired specimens from human HCC patients, and the adjacent, normal tissues exhibited a tumor-specific expression pattern which was highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. Therefore, our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression.

• DP1
• E2F1
• ISX
• cyclin D1
• hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit proliferation of human HCC cells, although the underlying mechanism(s) are unclear.

Protein expression was detected by Western blots. Cell viability was determined by using the CellTiter Assay kit.

We confirm that BBR treatment inhibits HepG2, Hep3B, and SNU-182 cell viability, and suggest that it regulates this proliferation via the modulation of multiple tumorigenesis-related genes protein expression. BBR treatment up-regulated protein expression of tumor suppressor genes, including Kruppel-like factor 6 (KLF6), activating transcription factor 3 (ATF3) and p21, while down-regulating the expression of selected oncogenes, including E2F transcription factor 1 (E2F1) and pituitary tumor transforming gene 1 (PTTG1). The specific extracellular signal–regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, partially inhibited BBR effects including reduction of cell viability, and up-regulation of KLF6 and ATF3 expressions; although, PD98059 did not alter the down-regulation of E2F1 and PTTG1 expression by BBR.

Our results suggest that BBR inhibits HCC cell viability by modulating multiple tumorigenesis-related genes, and that up-regulation of tumor suppressor genes by BBR is in part the result of ERK1/2 action. The results of this study augment our understanding of the mechanisms underlying the effect of BBR on hepatocellular cancers and provide further evidence as to the biological plausibility of this agent’s role in the treatment of these malignancies.

The online version of this article (doi:10.1186/s12935-017-0429-3) contains supplementary material, which is available to authorized users.

• ATF3
• Berberine
• E2F1
• ERK1/2
• Hepatocellular carcinoma
• KLF6
• PTTG1
• p21

• ITGA1
• d-ICD
• hepatocellular carcinoma
• invasion
• migration

The E2F proteins comprise a family of 8 members that function as transcription factors. They are key targets of the retinoblastoma protein (RB) and were initially divided into groups of activators and repressors. Accumulating data suggest that there is no specific role for each individual E2F member. Instead, each E2F can exert a variety of cellular effects, some of which represent opposing ones. For instance, specific E2Fs can activate transcription and repression, promote or hamper cell proliferation, augment or inhibit apoptosis, all being dependent on the cellular context. This complexity reflects the importance that these transcription factors have on a cell’s fate. Thus, delineating the specific role for each E2F member in specific malignancies, although not easy, is a challenging and continuously pursued task, especially in view of potential E2F targeted therapies. Therefore, several reviews are continuously trying to evaluate available data on E2F status in various malignancies. Such reviews have attempted to reach a consensus, often in the simplistic form of oncogenes or tumor suppressor genes for the E2Fs. However they frequently miss spatial and temporal alterations of these factors during tumor development, which should also be considered in conjunction with the status of the regulatory networks that these factors participate in. In the current ‘‘Letter to the Editor’’, we comment on the flaws, misinterpretations and omissions in one such review article published recently in the World Journal of Gastroenterology regarding the role of E2Fs in digestive system malignancies.

• E2F
• Hepatocellular carcinoma
• Pancreatic ductal adenocarcinoma
• Gastrointestinal tract
• Digestive system
• p53
• p73
• Cancer
• Apoptosis
• Proliferation

• Animals
• Carcinogenesis/metabolism
• Digestive System Neoplasms/metabolism
• E2F Transcription Factors/metabolism
• Humans

Classically, as a transcription factor family, the E2Fs are known to regulate the expression of various genes whose products are involved in a multitude of biological functions, many of which are deregulated in diseases including cancers. E2F is deregulated and hyperactive in most human cancers with context dependent, dichotomous and contradictory roles in almost all cancers. Cancer cells have an insatiable demand for transcription to ensure that gene products are available to sustain various biological processes that support their rapid growth and survival. In this context, cutting-off hyperactivity of transcription factors that support transcription dependence could be a valuable therapeutic strategy. However, one of the greatest challenges of targeting a transcription factor is the global effects on non-cancerous cells given that they control cellular functions in general. Recently, there is growing realization regarding the possibility to target the oncogenic activation of transcription factors to modulate transcription addiction without affecting the normal activity required for cell functions. In this review, we used E2F1 as a prototype transcription factor to address transcription factor activity in cancer cell functions. We focused on melanoma considering that E2F1 executes critical functions in response to UV, an etiological factor of cutaneous melanoma and lies immediately downstream of the CDKN2A/pRb axis, which is frequently deregulated in melanoma. Further, activation of E2F1 in melanomas can also occur independent of loss of CDKN2A. Given its activated status and the ability to transcriptionally control a plethora of genes involved in regulating melanoma development and progression, we review the current literature on its differential role in controlling signaling pathways involved in melanoma as well as therapeutic resistance, and discuss the practical value of weaning melanoma cells from E2F1-mediated transcription dependence for melanoma management.

• Adenoviridae
• Combined Modality Therapy
• Cytokine-Induced Killer Cells/immunology
• E2F1 Transcription Factor/biosynthesis
• E2F1 Transcription Factor/immunology
• Gene Expression Regulation, Neoplastic
• Humans
• Immunotherapy
• Oncolytic Virotherapy
• Oncolytic Viruses/immunology
• Promoter Regions, Genetic
• Rectal Neoplasms/immunology
• Rectal Neoplasms/therapy
• Rectal Neoplasms/virology

Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well-characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and β-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis.

• 26S proteasome
• Bortezomib
• Cyclins
• E2F family
• Hepatocellular carcinoma
• Liver
• Microarray

• Antineoplastic Agents/pharmacology
• Boronic Acids/pharmacology
• Bortezomib
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Proliferation/drug effects
• Cyclins/genetics
• Cyclins/metabolism
• E2F Transcription Factors/genetics
• E2F Transcription Factors/metabolism
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Phenotype
• Proteasome Inhibitors/pharmacology
• Pyrazines/pharmacology
• RNA Interference
• RNA, Messenger/metabolism
• Transfection

• Apoptosis
• Hepatocellular carcinoma
• Mammalian E2F family
• Proliferation
• Therapies

E2F family of transcription factors regulates various cellular functions related to cell cycle and apoptosis. Its individual members have traditionally been classified into activators and repressors, based on in vitro studies. However their contribution in human cancer is more complicated and difficult to predict. We review current knowledge on the expression of E2Fs in digestive system malignancies and its clinical implications for patient prognosis and treatment. E2F1, the most extensively studied member and the only one with prognostic value, exhibits a tumor-suppressing activity in esophageal, gastric and colorectal adenocarcinoma, and in hepatocellular carcinoma (HCC), whereas in pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma may function as a tumor-promoter. In the latter malignancies, E2F1 immunohistochemical expression has been correlated with higher tumor grade and worse patient survival, whereas in esophageal, gastric and colorectal adenocarcinomas is a marker of increased patient survival. E2F2 has only been studied in colorectal cancer, where its role is not considered significant. E2F4’s role in colorectal, gastric and hepatic carcinogenesis is tumor-promoting. E2F8 is strongly upregulated in human HCC, thus possibly contributing to hepatocarcinogenesis. Adenoviral transfer of E2F as gene therapy to sensitize pancreatic cancer cells for chemotherapeutic agents has been used in experimental studies. Other therapeutic strategies are yet to be developed, but it appears that targeted approaches using E2F-agonists or antagonists should take into account the tissue-dependent function of each E2F member. Further understanding of E2Fs’ contribution in cellular functions in vivo would help clarify their role in carcinogenesis.

• E2F
• Colorectal cancer
• Gastric cancer
• Esophageal cancer
• Pancreatic cancer
• Hepatocellular carcinoma
• Digestive system malignancies

• Animals
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Digestive System Neoplasms/genetics
• Digestive System Neoplasms/metabolism
• Digestive System Neoplasms/mortality
• Digestive System Neoplasms/pathology
• Digestive System Neoplasms/therapy
• E2F Transcription Factors/genetics
• E2F Transcription Factors/metabolism
• Humans
• Prognosis
• Signal Transduction