PO.CL04.01 · 临床研究
驱动p53缺失并决定膀胱癌侵袭性表型的新机制
Novel mechanism driving p53 loss that dictates bladder cancer aggressive phenotypes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
膀胱癌（BLCA）仍是一种临床异质性疾病，其特征为高突变负荷、高复发率以及晚期阶段的不良生存。识别疾病进展和治疗耐药的分子驱动因素对于改善患者预后至关重要。在肌层浸润性膀胱癌（MIBC）中，p53缺失是驱动侵袭性基底/鳞状样亚型的主要分子标志，赋予其对细胞杀伤的抵抗和免疫逃逸能力。然而，p53失活/缺失的潜在机制迄今尚未阐明。我们此前曾证明视网膜变性蛋白3（RD3）在体内广泛表达并发挥肿瘤保护作用。在本研究中，我们在107例BLCA患者队列中探讨了RD3缺失的临床意义及其与p53状态的相互关系。使用自建存档的组织微阵列，通过免疫组织化学分析了RD3的表达。与临床预后良好的非肌层浸润性膀胱癌（NMIBC）相比，我们在侵袭性BLCA肿瘤中观察到RD3的完全缺失。RD3缺失与晚期肿瘤分期（MIBC）、疾病播散、治疗耐药、转移和复发密切相关。生存分析显示，RD3缺陷病例的总生存（OS）、无进展生存（PFS）和无复发生存（RFS）呈现明显下降趋势。与此同时，同一队列中p53的表达也表现出相似的关联，证实p53受损是晚期BLCA的一个决定性特征。更重要的是，我们的研究结果表明RD3缺失与p53缺失呈线性关联。鉴于RD3作为调控p53竞争者NFκB的上游效应因子的功能，这些发现揭示了BLCA演进中RD3→p53的信号传导通路。这种双重缺失可能代表一个驱动BLCA疾病进展和治疗失败的协同轴。这些结果将RD3定位为一个潜在的预后生物标志物和治疗靶点，尤其是在p53缺陷型肿瘤中。我们研究目前的重点在于阐明RD3-p53调控网络及其对高危BLCA患者精准医学的意义。
资助：DoD CA-210339；OCAST-HR19-045；P20GM103639
查看英文原文 English abstract
Bladder cancer (BLCA) remains a clinically heterogeneous disease, characterized by high mutational burden, recurrence rates, and poor survival in advanced stages. Identifying molecular drivers of progression and therapy resistance is crucial for improving patient outcomes. In muscle-invasive bladder cancer (MIBC), loss of p53 is a major molecular hallmark that drives aggressive basal/squamous-like subtypes, conferring resistance to cell killing and immune evasion. However, the mechanisms underlying p53 inactivation/loss remain thus far unrealized. We previously showed that Retinal Degeneration Protein 3 (RD3) is widely expressed in the body and plays a tumor-protective role. In this study, we investigated the clinical significance of RD3 loss and its interplay with p53 status in a cohort of 107 BLCA patients. Using a custom-archived tissue microarray, RD3 expression was profiled (immunohistochemistry). We observed a complete loss of RD3 in aggressive BLCA tumors when compared with clinically favorable non-muscle invasive bladder cancer (NMIBC). RD3 loss strongly correlated with advanced tumor stage (MIBC), disease dissemination, therapy resistance, metastasis, and recurrence. Survival analysis indicated a strong trend toward decreased overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) in RD3-deficient cases. In parallel, p53 expression in the same cohort demonstrated similar associations, confirming that compromised p53 is a defining feature of advanced BLCA. More importantly, our findings indicate a linear association of RD3 loss with p53 loss. Owing to the upstream effector function of RD3 regulating p53 competitor NFκB, the findings throw light on the RD3→p53 signaling flow-through in BLCA evolution. This dual loss could represent a synergistic axis driving disease progression and therapeutic failure in BLCA. These results position RD3 as a potential prognostic biomarker and therapeutic target, especially in p53-deficient tumors. The current focus of our studies are in the line of delineating the RD3-p53 regulatory network and its implications for precision medicine for high-risk BLCA patients.
Funding: DoD CA-210339; OCAST-HR19-045; P20GM103639
利益披露 Disclosure
S. Salim, None..
S. Mohanvelu, None..
P. Subramanian, None..
A. Jahir Hussain, None..
S. Aravindan, None..
N. Aravindan, None.