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Author: Sophia
Introduction: As the most prominent RNA modification, N6-methyladenosine (m6A) is involved in the regulation of tumorigenesis and progression. Circular RNA (circRNA) also plays a vital role in ubiquitous life processes. Whether circRNA is required for m6A regulation of renal cell carcinoma (RCC) is unknown.
近日，华中科技大学同济医学院附属协和医院章小平和华中科技大学同济医学院基础医学院杨红枚共同通讯在期刊《Clinical and Translational Medicine》上发表题为“circRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma”的研究论文，研究结果阐明了IGF2BP3/circRARS复合物在RCC进展中的致癌功能，并为RCC患者提出了新的治疗靶点。
https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.1512
Background:
01
Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system, with an increasing incidence worldwide. In 2023, 81 800 new diagnoses and 14 890 RCC deaths are expected in the United States. Clear cell renal cell carcinoma (ccRCC) is the most prominent pathological subtype of renal cell carcinoma, characterized by strong migration and resistance to chemoradiotherapy. Most patients with advanced RCC develop resistance to targeted agents such as sunitinib within 6-15 months. Therefore, there is an urgent need to explore the mechanism of RCC progression and infer effective biomarkers in order to detect RCC and predict prognosis.
N6-methyladenosine (m6A) is the most prevalent internal modification in RNA and is critical in various malignancy-associated pathways. However, the potential role of m6A in the progression of RCC remains an open question. m6A is regulated by writer proteins, erasure proteins, and reader proteins. Among them, the insulin-like growth factor 2 mRNA-binding protein (IGF2BPs) family is an important reading protein. They contain multiple KH domains that bind to RNA and regulate RNA metabolism. In particular, IGF2BP3 is significantly upregulated in RCC and has been recommended as a prognostic biomarker in multiple clinical studies. IGF2BP3 can recognize m6A modification sequences and regulate mRNA stability and translation. It has been demonstrated that with the help of long non-coding RNAs (lncRNAs), CDK4 mRNA IGF2BP3 stabilized and RCC development is driven by m6A modification. However, the underlying mechanism IGF2BP3 recognize m6A modifications remains obscured. Whether other molecules are involved in regulating m6A recognition IGF2BP3 remains to be explored.
Research Progress
02
ACHN cells stably transfected IGF2BP3 sgRNA or control and circRARS or vehicle are injected into the left kidney capsule of 4-week-old nude mice for the construction of orthotopic xenograft models. Consistently, in vivo assays showed that IGF2BP3 knockdown attenuated RCC cancer stemness and inhibited the growth of orthotopic xenografts, while overexpression of circRARS impaired inhibition (Fig. 7A, B). In orthotopic xenografts, Western blotting and IHC assays showed that protein levels of CAPN15, CD44, HMGA2, TNRC6A, and ZMIZ2 were regulated by the IGF2BP3/circRARS complex (Figure 7C). IF shows that the IGF2BP3/circRARS complex promotes RCC cell proliferation. Ki67 is a biomarker of cell proliferation, and PAX8 positivity represents RCC cells (Figure 7D). The venous-tail tumor injection test showed that knockdown IGF2BP3 reduced lung metastases, while overexpression of circRARS promoted lung metastases (Figure 7E). H&E staining on nude mouse lungs suggests that the IGF2BP3/circRARS complex promotes the formation and proliferation of RCC lung metastases (Figure 7F,G). Finally, overexpression of IGF2BP3 can shorten the survival time of nude mice, which can be rescued by circRARS knockdown (Figure 7H). In summary, the carcinogenic properties of the IGF2BP3/circRARS complex in RCC were verified in vivo.
IGF2BP3/circRARS complex promotes RCC progression in vivo
Findings:
03
In this study, meta-analysis and bioinformatics found that IGF2BP3 was upregulated in RCC, indicating a worse prognosis. IGF2BP3 significantly contributed to the progression of RCC in vitro and in vivo. Mechanistically, circRARS binds to the IGF2BP3 of the KH1–KH2 domain to enhance m6A modification recognition. The 12-nt sequence (GUCUUCCAGCAA) was shown to be a IGF2BP3 binding site for circRARS. In addition, CAPN15, CD44, HMGA2, TNRC6A, and ZMIZ2 were screened as target genes regulated by the IGF2BP3/circRARS complex in an m6A-dependent manner. circRARS recruited stable proteins, including HuR, Matrin3, and pAbPC1, thereby improving the mRNA stability of the five target genes mentioned above. Thus, the IGF2BP3/circRARS complex promotes lipid accumulation in RCC cells and promotes sunitinib resistance through target genes. circRARS synergistically promotes m6A recognition with IGF2BP3, thereby promoting RCC progression. Therefore, IGF2BP3 may be a potential biomarker for the diagnosis and prognosis of RCC as well as a therapeutic target.
Resources:
https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.1512
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please visit a regular hospital.
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