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SPTBN1 abrogates renal clear cell carcinoma progression via glycolysis reprogramming in a GPT2-dependent manner
Jiajin Wu1, Chenkui Miao1, Yuhao Wang1
1Department of Urology, The First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, No. 300 Guangzhou Road, Nanjing, 210029, China.
Background:
Renal clear cell carcinoma (ccRCC) is the most prevalent tumors worldwide. Discovering effective biomarkers is essential to monitor the prognosis and provide alternative clinical options. SPTBN1 is implicated in various cancerous processes. However, its role in ccRCC remains unelucidated. This study intends to explore the biological function and mechanism of SPTBN1 in ccRCC.
Methods:
Single-cell and bulk RNA-seq, tissue microarray, real-time quantitative PCR, and western blotting were applied to verify the expression and predictive value of SPTBN1 in ccRCC. Gain or loss of functional ccRCC cell line models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Actinomycin D experiment, RNA immunoprecipitation (RIP), specific inhibitors, and rescue experiments were carried out to define the molecular mechanisms.
Results:
SPTBN1 was down-regulated in ccRCC and knockdown of SPTBN1 displayed a remarkably oncogenic role both in vitro and in vivo; while overexpressing SPTBN1 reversed this effect. SPTBN1 mediated ccRCC progression via the pathway of glutamate pyruvate transaminase 2 (GPT2)-dependent glycolysis. The expression of GPT2 was significantly negatively correlated with that of SPTBN1. As an RNA binding protein SPTBN1, regulated the mRNA stability of GPT2.
Conclusion:
Our research demonstrated that SPTBN1 is significantly down-regulated in ccRCC. SPTBN1 knockdown promotes ccRCC progression via activating GPT2-dependent glycolysis. SPTBN1 may serve as a therapeutic target for the treatment of ccRCC.
Insights
SPTBN1 is down-regulated in kidney cancer (ccRCC). Its loss promotes tumor growth by activating glycolysis, suggesting SPTBN1 as a potential therapeutic target for ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Renal clear cell carcinoma (ccRCC) is the most common kidney cancer.
- Identifying prognostic biomarkers is crucial for ccRCC management.
- The role of SPTBN1 in ccRCC pathogenesis was previously unknown.
Purpose of the Study:
- To investigate the biological function and molecular mechanism of SPTBN1 in ccRCC.
- To determine the potential of SPTBN1 as a biomarker or therapeutic target for ccRCC.
Main Methods:
- Utilized single-cell and bulk RNA sequencing, tissue microarrays, qPCR, and Western blotting to assess SPTBN1 expression.
- Generated and analyzed ccRCC cell line models with SPTBN1 gain or loss of function.
- Conducted in vitro and in vivo assays, along with molecular experiments (Actinomycin D, RIP, inhibitor studies, rescue experiments) to elucidate mechanisms.
Main Results:
- SPTBN1 expression was found to be significantly downregulated in ccRCC tissues.
- Knockdown of SPTBN1 promoted ccRCC cell proliferation and tumor growth in vitro and in vivo.
- Overexpression of SPTBN1 inhibited ccRCC progression.
- SPTBN1 regulates ccRCC progression through the GPT2-dependent glycolysis pathway.
- SPTBN1, as an RNA-binding protein, controls GPT2 mRNA stability, with GPT2 expression inversely correlated to SPTBN1.
Conclusions:
- SPTBN1 is significantly downregulated in ccRCC and acts as a tumor suppressor.
- SPTBN1 knockdown promotes ccRCC progression by activating GPT2-dependent glycolysis.
- SPTBN1 represents a potential therapeutic target for ccRCC treatment.
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