中山大学Xiao-lei Zhang和Yan-dong Wang共同合作，近期取得重要工作进展。他们研究提出，Zhang, Xiao-lei团队取得一项新突破。他们的研究发现新的STAT3寡核苷酸化合物抑制肿瘤生长，并克服肝细胞癌对索拉非尼的获得性耐药性。相关论文发表在2024年4月12日出版的《中国药理学报》杂志上。

据介绍，信号转导器和转录激活因子3（STAT3）在肿瘤的发生和发展中起着重要作用，会导致耐药性和不良预后的发生。在肝细胞癌（HCC）中经常检测到STAT3信号的激活，但尚未发现有效且毒性较小的STAT3抑制剂。

在反义技术的基础上，研究人员设计了一系列稳定的修饰反义寡核苷酸，靶向STAT3 mRNA（STAT3 ASO）。STAT3 ASO治疗降低了HCC细胞中STAT3 mRNA和蛋白质水平。STAT3 ASO通过特异性干扰STAT3信号传导，显著抑制癌症细胞的增殖、存活、迁移和侵袭。STAT3 ASO治疗降低了HCC异种移植物模型中的肿瘤负担。

此外，异常STAT3信号激活是参与HCC中sorafenib（索拉非尼）耐药性的多种信号通路之一。STAT3 ASO在体外有效地使耐药HCC细胞系对索拉非尼敏感，并在耐药HCC异种移植模型中提高索拉非尼的抑制效力。

总之，这一研究开发的STAT3 ASO丰富了能够靶向STAT3和调节STAT3活性的工具，是治疗HCC和其他STAT3成瘾性肿瘤的一种有前途的策略，并减轻HCC患者对索拉非尼的获得性耐药。

附：英文原文

Title: Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma

Author: Zhang, Qi-yi, Ding, Wen, Mo, Jian-shan, Ou-yang, Shu-min, Lin, Zi-you, Peng, Ke-ren, Liu, Guo-pin, Lu, Jin-jian, Yue, Pei-bin, Lei, Jin-ping, Wang, Yan-dong, Zhang, Xiao-lei

Issue&Volume: 2024-04-12

Abstract: Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients.

DOI: 10.1038/s41401-024-01261-4

Source: https://www.nature.com/articles/s41401-024-01261-4