ZDHHC15 regulates YAP localization and YAP/CYR61 signaling in OSCC. • PA supports OSCC migration through lipid metabolism-linked signaling. • R-LPA@siZDHHC15 enables targeted siRNA delivery and photothermal response. • The nanoplatform suppresses OSCC growth and lung colonization in models. This study aimed to elucidate the molecular mechanism by which ZDHHC15 promotes oral squamous cell carcinoma (OSCC) progression through regulation of the YAP/CYR61 signaling axis. Metabolomic and transcriptomic analyses revealed prominent lipid metabolic reprogramming in OSCC cells, with palmitic acid (PA) driving activation of the YAP transcriptional program and promoting cell migration and lung colonization. Functional experiments showed that ZDHHC15 enhanced YAP nuclear localization and transcriptional activity, leading to increased CYR61 expression and establishment of the ZDHHC15/YAP/CYR61 signaling axis. In addition, we developed a novel nanoplatform, R-LPA@siZDHHC15, which exhibited photothermal responsiveness and tumor-targeted delivery in vivo . When combined with photothermal therapy, this platform suppressed OSCC cell proliferation and tumor growth under the tested conditions. Collectively, these findings provide mechanistic insight into OSCC progression and support targeting the ZDHHC15/YAP/CYR61 axis as a potential therapeutic strategy, while further control and thermal-monitoring studies are needed to fully define the nanotherapeutic contribution. Schematic representation of the molecular mechanism by which R-LPA@siZDHHC15 modulates the YAP/CYR61 axis, thereby achieving combined photothermal and gene therapy to suppress OSCC progression. Download: Download high-res image (152KB) Download: Download full-size image
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high incidence and mortality. MiR-597-5p is downregulated in tumor tissues of HCC compared with non-tumor tissues. However, its role in HCC is still unknown. This study aims to assess the function of miR-597-5p in HCC development and investigate the underlying mechanism. To perform gain- and loss-of-function studies, SK-HEP-1 cells and Huh-7 cells were transfected with miR-597-5p mimics and inhibitor, respectively. MiR-597-5p markedly reduced the cell viability and the expression of Ki-67 in HCC cells. MiR-597-5p also repressed the cell cycle progression of HCC cells and the protein levels of cyclin D1 and CDK2. Moreover, miR597-5p inhibited the migration and invasion of HCC cells and decreased MMP2 and MMP9 levels. Transcriptional enhancer associate domain transcription factor 1 (TEAD1) was identified as a target of miR-597-5p by luciferase reporter assay. TEAD1 and its downstream target genes, CTGF and CYR61, were downregulated by miR-597-5p in HCC cells. Furthermore, miR-597-5p was demonstrated to function in HCC progression by targeting TEAD1 via TEAD1 expression gain and loss. Our study demonstrates that miR-597-5p represses the proliferation, migration, and invasion of HCC cells through targeting TEAD1, which provides a therapeutic target for HCC treatment.
Background Studies have shown that phenylethanoid glycosides (PhGs) have multiple pharmacological effects such as anti-inflammatory, hepatoprotective or neuroprotective functions, whereas their anti-tumor effects are rarely studied. Tubuloside B (Tub B) is a PhG isolated from Cistanche deserticola , a traditional Chinese medicine. To date, there is a lack of comprehensive research regarding the biological activity of Tub B. Purpose The subject of the current study was to investigate the anti-hepatocellular carcinoma (HCC) cell activity and the underlying mechanism of Tub B. Methods We evaluated the in vitro anti-migratory effect of Tub B by scratch and transwell assays. RNA-seq was employed to identify the differential genes by Tub B. Besides, the functional mechanism of Tub B was investigated by distinct molecular biology techniques including immunofluorescent staining, quantitative PCR, as well as western blot analysis. Subsequently, we utilized Hep3B cells for in vivo metastasis assays through spleen injection and evaluated the anti-migratory effect of Tub B in hepatocellular carcinoma (HCC). Results Tub B exhibited in vitro and in vivo inhibition of HCC cell migration. Tub B decreased the expression of transcriptional target genes downstream of the Hippo pathway, including CTGF, CYR61, and N-cadherin as determined by RNA-seq. Furthermore, mechanistic studies confirmed that Tub B increased phosphorylation of YAP at S127, which contributes to YAP cytoplasmic localization. Additionally, overexpression of YAP abrogated Tub B-induced inhibition of HCC migration and the mRNA levels of CTGF, CYR61, and N-cadherin . Conclusions Taken together, these results illustrated that Tub B demonstrated great potential in inhibiting migration of HCC, and a portion of its impact can be attributed to the modulation of the Hippo-YAP pathway.
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