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Published on: April 7, 2017
E2F1 and E2F7 regulate gastric cancer cell proliferation, respectively, through transcriptional activation and
Tianyi Wu1, Fengli Jiang2, Fan Wu1
1Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Abstract:
Gastric cancer (GC) is the most common malignant tumor of the digestive tract. However, the molecular pathogenesis is not well understood. Through bioinformatic analysis and analyzing clinical tissue samples, we found that E2F1 and E2F7 as well as their potential downstream target MYBL2 were all upregulated in GC tissues and that their expressions correlated with patient prognosis. While knockdown of E2F1 or MYBL2 inhibited cell proliferation and promoted apoptosis, knockdown of E2F7 promoted cell proliferation but had no effects on apoptosis. Chromatin immunoprecipitation and dual luciferase reporter assays demonstrated that MYBL2 was transcriptionally activated and repressed by E2F1 and E2F7, respectively. Importantly, in vitro and ex vivo experiments demonstrated that the effects of E2F1 and E2F7 on GC cell proliferation were significantly attenuated by reversely modulating MYBL2 expression, indicating that MYBL2 is a direct and functionally relevant target of E2F1 and E2F7 in GC cells. Furthermore, the effects of E2F1 and E2F7 on GC cell proliferation through transcriptional regulation of MYBL2 can be mediated by the PI3K/AKT signaling pathway. Interestingly, we found differential nucleocytoplasmic distribution of E2F7 in GC cells with functional relevance. Taken together, our data suggest that targeted therapies of GC may be achieved from three different angles, E2F1, E2F7, and MYBL2 themselves, E2F1/E2F7 expression balance, and E2F7 nuclear localization.
Insights
This study reveals E2F1, E2F7, and MYBL2 are upregulated in gastric cancer (GC), impacting patient prognosis. Targeting these factors or their balance offers potential new therapies for GC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer (GC) is a prevalent digestive tract malignancy with poorly understood molecular drivers.
- Identifying key molecular players is crucial for developing effective targeted therapies.
Purpose of the Study:
- To investigate the roles of E2F1, E2F7, and MYBL2 in gastric cancer pathogenesis.
- To elucidate the regulatory mechanisms and therapeutic potential of targeting these factors in GC.
Main Methods:
- Bioinformatic analysis of GC tissues.
- Gene expression analysis and correlation with patient prognosis.
- In vitro and ex vivo cell culture experiments, including gene knockdown and chromatin immunoprecipitation assays.
- Analysis of the PI3K/AKT signaling pathway and E2F7 nucleocytoplasmic distribution.
Main Results:
- E2F1, E2F7, and MYBL2 were found to be upregulated in GC tissues, correlating with poorer patient outcomes.
- E2F1 and MYBL2 knockdown inhibited GC cell proliferation and induced apoptosis, while E2F7 knockdown promoted proliferation.
- MYBL2 acts as a direct transcriptional target of both E2F1 (activation) and E2F7 (repression), mediating their effects on cell proliferation via the PI3K/AKT pathway.
- Differential nucleocytoplasmic distribution of E2F7 was observed in GC cells.
Conclusions:
- MYBL2 is a key downstream effector of E2F1 and E2F7 in regulating gastric cancer cell proliferation.
- Targeting E2F1, E2F7, MYBL2, their expression balance, or E2F7 localization presents novel therapeutic strategies for gastric cancer.
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