Wang Xiangling, Chai Rundong, Li Jiaying, Chen Yinxiao, Li Zhaodong, Bian Yuhong, Zhao Shuwu
College of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No. 10 Poyanghu Road, JingHai District, Tianjin, 301617, China.
Naturwissenschaften. 2025 Jun 4;112(4):47. doi: 10.1007/s00114-025-01988-y.
Our previous research demonstrated that curcumin suppresses mouse colorectal cancer (CRC) cell CT26 migration and invasion by inhibiting heparanase (HPSE) mRNA expression. To further elucidate the mechanism of curcumin in human CRC treatment, we hypothesized that HPSE plays a pivotal role in human CRC metastasis and that curcumin inhibits this process by downregulating HPSE expression through epigenetic regulation mediated by non-coding RNAs. For further research, human CRC cells were infected with lentivirus to establish overexpression of HPSE cell lines and corresponding negative control cell lines. In vitro and in vivo experiments showed that curcumin inhibited the proliferation, migration, and metastasis of CRC cancer by inhibiting HPSE expression. In the tumor microenvironment, HPSE played an important role in activating the IL-6/STAT5 axis signaling pathway by destructing the extracellular matrix and releasing large number of cytokines, while changing the tumor microenvironment and EMT process, thus promoting tumor metastasis. RNA-seq analysis combined with qRT-PCR results showed that curcumin's inhibition of HPSE expression involved the regulation of non-coding RNAs. Taken together, our results suggested that HPSE promotes CRC metastasis by activating the IL-6/STAT5 signaling axis, disrupting the ECM, releasing cytokines, and altering the tumor microenvironment to facilitate EMT. Curcumin significantly inhibits CRC cell proliferation, migration, and metastasis by downregulating HPSE expression via non-coding RNAs, which related to IL-6/STAT5 axis signal pathways. This research provides a comprehensive understanding of the molecular mechanisms underlying curcumin's anti-CRC effects, emphasizing the role of HPSE and non-coding RNAs in tumor metastasis. These findings pave the way for the development of novel therapeutic strategies targeting HPSE and its regulatory pathways in CRC.
我们之前的研究表明，姜黄素通过抑制乙酰肝素酶（HPSE）mRNA表达来抑制小鼠结直肠癌（CRC）细胞CT26的迁移和侵袭。为了进一步阐明姜黄素在人类CRC治疗中的作用机制，我们假设HPSE在人类CRC转移中起关键作用，并且姜黄素通过非编码RNA介导的表观遗传调控下调HPSE表达来抑制这一过程。为了进一步研究，用慢病毒感染人CRC细胞以建立HPSE过表达细胞系和相应的阴性对照细胞系。体外和体内实验表明，姜黄素通过抑制HPSE表达来抑制CRC的增殖、迁移和转移。在肿瘤微环境中，HPSE通过破坏细胞外基质并释放大量细胞因子，在激活IL-6/STAT5轴信号通路中起重要作用，同时改变肿瘤微环境和EMT过程，从而促进肿瘤转移。RNA测序分析结合qRT-PCR结果表明，姜黄素对HPSE表达的抑制涉及非编码RNA的调控。综上所述，我们的结果表明，HPSE通过激活IL-6/STAT5信号轴、破坏细胞外基质、释放细胞因子以及改变肿瘤微环境以促进EMT来促进CRC转移。姜黄素通过非编码RNA下调HPSE表达，显著抑制CRC细胞的增殖、迁移和转移，这与IL-6/STAT5轴信号通路有关。本研究全面了解了姜黄素抗CRC作用的分子机制，强调了HPSE和非编码RNA在肿瘤转移中的作用。这些发现为开发针对CRC中HPSE及其调控途径的新型治疗策略铺平了道路。
