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Abstract：
Colorectal cancer (CRC) remains a major global cause of cancer-related mortality, lacking effective biomarkers and therapeutic targets. Revealing the critical pathogenic factors of CRC and the underlying mechanisms would offer potential therapeutic strategies for clinical application. G protein signaling (RGS) protein family modulators play essential role within regulating downstream signaling of GPCR receptors, with function in cancers unclear. Our study focused on the expression patterns of RGS proteins in CRC, identifying Regulator of G protein signaling 16 (RGS16) as a prospective diagnostic and therapeutic target. Analyzing 899 CRC tissues revealed elevated RGS16 levels, correlating with clinicopathological features and CRC prognosis by immunohistochemistry (IHC) combined with microarray. We confirmed the elevated RGS16 protein level in CRC, and found that patients with RGS16-high tumors exhibited decreased disease-specific survival (DSS) and disease-free survival (DFS) compared to those with low RGS16 expression. Functional assays demonstrated that RGS16 promoted the CRC progression, knockdown of RGS16 led to significantly increased apoptosis rates of CRC in vitro and in vivo. Notably, we also confirmed these phenotypes of RGS16 in organoids originated from resected primary human CRC tissues. Mechanistically, RGS16 restrained JNK/P38-mediated apoptosis in CRC cells through disrupting the recruitment of TAB2/TAK1 to TRAF6. This study provides insights into addressing the challenges posed by CRC, offering avenues for clinical translation.
摘要：
结直肠癌（CRC）仍然是全球癌症相关死亡的主要原因。缺乏有效的生物标志物和治疗靶点。揭示CRC的关键致病因素和潜在机制将为临床应用提供潜在的治疗策略。G蛋白信号（RGS）蛋白家族调节剂在调节GPCR受体的下游信号中起重要作用，在癌症中的功能不清楚。我们的研究集中在CRC中RGS蛋白的表达模式，确定G蛋白信号调节因子16（RGS16）作为一个前瞻性的诊断和治疗靶标。分析899个CRC组织显示RGS16水平升高，通过免疫组织化学（IHC）结合微阵列与临床病理特征和CRC预后相关。我们证实了CRC中RGS16蛋白水平的升高，发现与RGS16低表达的患者相比，RGS16高肿瘤患者的疾病特异性生存率（DSS）和无病生存率（DFS）降低。功能测定表明RGS16促进CRC进展，RGS16的敲低导致CRC在体外和体内的凋亡率显着增加。值得注意的是,我们还证实了RGS16在源自切除的原发性人类CRC组织的类器官中的这些表型。机械上,RGS16通过破坏TAB2/TAK1募集至TRAF6来抑制JNK/P38介导的CRC细胞凋亡。这项研究提供了解决CRC带来的挑战的见解，为临床翻译提供途径。
