Effect of ciRS-7 Expression on Clear Cell Renal Cell Carcinoma Progression
Clear cell renal cell carcinoma (ccRCC) remains a significant health burden due to its high recurrence rate and resistance to conventional chemotherapy and targeted therapies. While risk factors such as obesity, tobacco use, and hypertension contribute to its development, genetic mutations and abnormal post-translational protein modifications also play crucial roles in tumorigenesis. For instance, mutations in the von Hippel-Lindau (VHL) gene are common in ccRCC patients and are associated with tumor metastasis through angiogenesis. Despite advances in understanding ccRCC pathogenesis, effective systemic therapies for advanced ccRCC are still lacking. This has prompted researchers to explore novel molecular mechanisms that could provide new therapeutic targets.
Circular RNAs (circRNAs) are a class of non-coding RNAs characterized by their closed-loop structure, which confers stability against degradation. Recent studies have revealed that circRNAs are involved in various biological processes, including cell proliferation and angiogenesis. Among these, ciRS-7 (also known as cerebellar-degeneration-related protein 1 antisense RNA) has emerged as a key player in cancer progression. ciRS-7 acts as an oncogene by inhibiting the tumor suppressor miR-7 and has been implicated in the progression of several cancers, including hepatocellular carcinoma, gastric cancer, and non-small cell lung cancer. However, its role in ccRCC remains poorly understood.
This study aimed to investigate the expression and functional role of ciRS-7 in ccRCC progression, as well as the underlying molecular mechanisms. The research was conducted using a combination of clinical samples, cell culture experiments, and molecular biology techniques to provide a comprehensive understanding of ciRS-7’s impact on ccRCC.
The study analyzed ciRS-7 expression in 87 pairs of ccRCC tissues and matched adjacent normal tissues using quantitative reverse transcription polymerase chain reaction (qPCR). The results revealed that ciRS-7 was significantly overexpressed in ccRCC tissues compared to normal tissues. This upregulation was closely associated with advanced pathological features, including larger tumor diameter, higher clinical stage, and distant metastasis. Specifically, ciRS-7 expression was significantly higher in patients with clinical stage III and IV tumors compared to those with stage I and II tumors. Additionally, patients with high ciRS-7 expression had a shorter progression-free survival (PFS), as demonstrated by Kaplan-Meier analysis. These findings suggest that ciRS-7 could serve as a prognostic marker for ccRCC.
To further explore the functional role of ciRS-7 in ccRCC, the researchers conducted in vitro experiments using two ccRCC cell lines, 786O and 769P, and a normal renal tubular epithelial cell line, HK-2. qPCR analysis confirmed that ciRS-7 expression was significantly higher in both ccRCC cell lines compared to HK-2 cells. The researchers then silenced ciRS-7 expression in 786O and 769P cells using small interfering RNAs (siRNAs) and assessed the effects on cell proliferation and invasion.
Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay. The results showed that silencing ciRS-7 significantly inhibited the proliferative ability of both 786O and 769P cells. Similarly, transwell invasion assays demonstrated that ciRS-7 knockdown reduced the invasive capacity of these cells. These findings indicate that ciRS-7 plays a crucial role in promoting ccRCC cell proliferation and invasion, which are key processes in tumor progression.
To elucidate the molecular mechanisms underlying ciRS-7’s oncogenic effects, the researchers investigated its impact on the epidermal growth factor receptor (EGFR)/Akt signaling pathway. Western blot analysis revealed that ciRS-7 silencing led to a reduction in phosphorylated EGFR (p-EGFR) and phosphorylated Akt (p-Akt) levels, while total EGFR and Akt expression remained unchanged. This suggests that ciRS-7 promotes ccRCC progression by activating the EGFR/Akt signaling pathway, which is known to play a critical role in cell proliferation, invasion, and other malignant behaviors.
The EGFR/Akt pathway is a well-established driver of cancer progression, and its activation is often associated with poor prognosis in various malignancies. In ccRCC, EGFR activation has been linked to tumor growth and metastasis, making it a potential therapeutic target. The findings of this study suggest that ciRS-7 may serve as a novel therapeutic target in ccRCC by modulating this pathway. However, further research is needed to fully understand the mechanisms by which ciRS-7 activates EGFR/Akt signaling and to explore its potential as a therapeutic target in clinical settings.
In conclusion, this study provides compelling evidence that ciRS-7 is overexpressed in ccRCC and is associated with advanced disease features and poor prognosis. The functional experiments demonstrate that ciRS-7 promotes ccRCC cell proliferation and invasion, likely through activation of the EGFR/Akt signaling pathway. These findings highlight the potential of ciRS-7 as both a prognostic marker and a therapeutic target in ccRCC. Future studies should focus on validating these results in larger patient cohorts and exploring the therapeutic potential of targeting ciRS-7 in ccRCC treatment.
doi.org/10.1097/CM9.0000000000000867
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