He Cheng, Tang Chuanyu, Guo Jie, Yin Xiangyi, Zhu Qing, Fang Chihua
Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, 510280, China.
J Transl Med. 2025 Aug 19;23(1):939. doi: 10.1186/s12967-025-06983-5.
Pancreatic cancer (PC) is highly aggressive and fatal and has dismal prognostic outcomes, primarily due to its late-stage diagnosis and limited effective treatments. The molecular mechanisms triggering PC progression are largely unclear. This study investigated how CX26 contributes to pancreatic cancer development and its potential as a therapeutic target.
CX26 expression in PC and its clinical significance were examined through bioinformatics analysis. The biological functions of CX26 in PC cells were explored via colony formation, CCK-8, and proteomic analysis. To explore the mechanisms by which CX26 regulates c-Myc stability, co-immunoprecipitation, immunofluorescence, and molecular docking were utilized to investigate the interactions among CX26, PSMD2, and c-Myc. Additionally, subcutaneous xenografts in nude mice were applied to assess the impact of CX26 on PC progression in vivo.
Bioinformatics analysis indicated the upregulation of CX26 in PC tissues. In addition, CX26 expression was closely related to dismal prognostic outcomes. Further study revealed that CX26 promotes PC progression in vitro and in vivo. Proteomic analysis identified c-Myc as the key downstream target of CX26. Mechanistically, CX26 indirectly regulated c-Myc stability via PSMD2 rather than directly interacting with c-Myc. Moreover, CX26 competes with c-Myc to bind to the Armadillo-like helical domain of PSMD2, thereby preventing c-Myc proteasomal degradation.
This study suggests that CX26 facilitates PC progression by stabilizing c-Myc through competitively inhibiting the binding of PSMD2 to c-Myc. Given the challenges in directly inhibiting c-Myc, this novel regulatory mechanism provides valuable insights into PC biology and reveals that targeting CX26 is a possible way to promote c-Myc degradation and suppress PC growth.
胰腺癌（PC）具有高度侵袭性和致命性，预后结果不佳，主要原因是其晚期诊断和有效的治疗方法有限。引发胰腺癌进展的分子机制在很大程度上尚不清楚。本研究调查了CX26如何促进胰腺癌的发展及其作为治疗靶点的潜力。
通过生物信息学分析检测CX26在胰腺癌中的表达及其临床意义。通过集落形成、CCK-8和蛋白质组学分析探索CX26在胰腺癌细胞中的生物学功能。为了探究CX26调节c-Myc稳定性的机制，利用免疫共沉淀、免疫荧光和分子对接研究CX26、PSMD2和c-Myc之间的相互作用。此外，将裸鼠皮下异种移植用于评估CX26对体内胰腺癌进展的影响。
生物信息学分析表明CX26在胰腺癌组织中上调。此外，CX26表达与不良预后结果密切相关。进一步研究表明，CX26在体外和体内均促进胰腺癌进展。蛋白质组学分析确定c-Myc是CX26的关键下游靶点。机制上，CX26通过PSMD2间接调节c-Myc稳定性，而非直接与c-Myc相互作用。此外，CX26与c-Myc竞争结合PSMD2的犰狳样螺旋结构域，从而防止c-Myc被蛋白酶体降解。
本研究表明，CX26通过竞争性抑制PSMD2与c-Myc的结合来稳定c-Myc，从而促进胰腺癌进展。鉴于直接抑制c-Myc存在挑战，这种新的调节机制为胰腺癌生物学提供了有价值的见解，并表明靶向CX26是促进c-Myc降解和抑制胰腺癌生长的一种可能途径。
