DLG7/DLGAP5 as a Potential Therapeutic Target in Gastric Cancer
Gastric cancer remains one of the most aggressive and lethal malignancies worldwide, with an estimated 1.09 million new cases and 770,000 deaths reported in 2020 alone. Advanced stages of the disease often preclude surgical intervention, leaving chemotherapy as the primary treatment option. However, the survival outcomes for patients with advanced gastric cancer remain dismal, underscoring the urgent need for novel therapeutic targets and more effective treatment strategies. This study investigates the role of Disc large homolog 7 (DLG7) and its encoding gene, DLG associated protein 5 (DLGAP5), in gastric cancer progression and explores their potential as therapeutic targets.
DLG7, a microtubule-associated protein encoded by the DLGAP5 gene, plays a critical role in chromosome rearrangement and gene stability. Dysregulation of DLGAP5 expression has been implicated in carcinogenesis, with studies reporting its overexpression in various cancers, including gastric cancer. However, the specific mechanisms by which DLGAP5 contributes to gastric cancer development and progression remain poorly understood. This study aims to elucidate the functional role of DLGAP5 in gastric cancer and evaluate its potential as a therapeutic target.
The study was conducted with ethical approval from the People’s Hospital of Tibet Autonomous Region, and informed consent was obtained from all participants. Six pairs of gastric cancer tissues and adjacent normal tissues were collected from patients undergoing surgical treatment. The expression levels of DLGAP5 mRNA and DLG7 protein were analyzed using quantitative methods. Results revealed that both DLGAP5 mRNA and DLG7 protein levels were significantly elevated in gastric cancer tissues compared to adjacent normal tissues, confirming the gene’s overexpression in gastric cancer. Western blot analysis further demonstrated that DLG7 protein levels were higher in gastric cancer cell lines MKN-45, BGC-823, and MGC-803 compared to normal gastric epithelial cells GES1, with statistical significance (P < 0.010). These findings align with previous studies that identified DLGAP5 as a gene selectively upregulated in gastric cancer tissues.
To investigate the functional role of DLGAP5 in gastric cancer, DLGAP5 shRNA (shDLGAP5) was introduced into MKN and MGC cells using lentivirus infection. The impact of DLGAP5 knockdown on cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay. Results showed a significant reduction in the proliferation ability of DLGAP5 knockdown cells at 48, 72, and 96 hours compared to control cells (P < 0.010), suggesting that DLGAP5 overexpression promotes gastric cancer cell proliferation. This finding is consistent with previous studies demonstrating that DLGAP5 enhances the proliferative capacity of human cells. Furthermore, DLG7 is known to stabilize the oncoprotein Gankyrin, which facilitates the ubiquitination and degradation of the tumor suppressor protein p53. The overexpression of DLGAP5 likely contributes to the accumulation of Gankyrin, thereby promoting p53 degradation and supporting cancer cell proliferation.
The study also evaluated the effects of DLGAP5 knockdown on the migration and invasion abilities of gastric cancer cells. Scratch assays revealed that the migration ability of MKN and MGC cells was significantly reduced following DLGAP5 knockdown (P < 0.050), with no significant changes observed in the negative control group. Similarly, Transwell invasion experiments demonstrated that DLGAP5 knockdown significantly inhibited the invasive capacity of these cells. These findings suggest that DLGAP5 plays a critical role in promoting the migration and invasion of gastric cancer cells, a phenomenon previously observed in other cancers such as non-small cell lung cancer.
To further validate the role of DLGAP5 in gastric cancer progression, an in vivo tumor model was established using nude mice. Normal MGC cells (NC-NM), MGC cells infected with negative shRNA (NS-NM), and MGC cells infected with shDLGAP5 were injected into nude mice to assess tumor growth. Results showed that tumor size was significantly reduced in the shDLGAP5 group compared to the NC-NM group, while no significant changes were observed in the NS-NM group. Immunohistochemistry analysis revealed a significant reduction in Ki-67 protein expression in the shDLGAP5 group, indicating decreased tumor cell proliferation. Additionally, hematoxylin and eosin staining demonstrated a reduction in tumor blood vessels and angiogenesis in the shDLGAP5 group compared to the NC-NM group. Immunohistochemistry further confirmed a significant decrease in vascular endothelial growth factor (VEGF) expression in the shDLGAP5 group, suggesting that DLGAP5 knockdown inhibits angiogenesis in gastric cancer.
In conclusion, this study provides compelling evidence that DLG7/DLGAP5 plays a critical role in the growth, migration, invasion, and angiogenesis of gastric cancer cells. Knockdown of DLGAP5 significantly inhibits these processes both in vitro and in vivo, highlighting its potential as a therapeutic target for gastric cancer. The overexpression of DLGAP5 likely contributes to gastric cancer progression by promoting cell proliferation, migration, invasion, and angiogenesis, making it a promising candidate for targeted therapy. Further research is warranted to explore the clinical applications of DLGAP5 inhibition in gastric cancer treatment.
This study was supported by the Key Technology Projects of Tibet Autonomous Region, the PostDoctor Research Project at West China Hospital, Sichuan University, and the China Postdoctoral Science Foundation. The authors declare no conflicts of interest.
doi.org/10.1097/CM9.0000000000001859
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