Panoply™ Human ERBB3 Over-expressing Stable Cell Line

Ovarian cancer (OC) is the most common gynecological malignancy worldwide. Here, researchers found that CYLD levels were significantly reduced in cisplatin (DDP)-resistant cancer tissues and cells compared to normal tissues and cells. Knockdown of CYLD in DDP-sensitive cells was sufficient to transform them into DDP-resistant cells, the mechanism of which was to reduce apoptosis by increasing Bcl-XL and inhibiting Bax, and to increase drug efflux by upregulating ABCB1 expression. HER3 expression levels were substantially higher in resistant cancer tissues and cells, and HER3 was the upstream facilitator of suppressing CYLD expression via STAT3 signaling. Furthermore, in both in vitro and in vivo experiments, overexpression of CYLD in drug-resistant cells enhanced their sensitivity to platinum-based chemotherapy. ABCB1 is a key downstream target of CYLD in regulating tumor growth and treatment resistance; CYLD knockdown promotes p65 translocation to the nucleus and increases ABCB1 expression through transcriptional activation. High HER3 expression levels led to the inhibition of CYLD expression, thereby mediating cisplatin (DDP) resistance in ovarian cancer cells by blocking the apoptosis pathway and promoting drug efflux. These findings reveal a novel HER3/CYLD/ABCB1 axis that regulates tumor growth and DDP resistance, which may become a potential new therapeutic target for overcoming DDP resistance in ovarian cancer.

Researchers first examined the mRNA expression levels of HER family members (including EGFR, HER2, HER3, and HER4) in ovarian tumor tissues. They found a significant negative correlation between HER3 expression and CYLD expression (Figure 1A), but no correlation with the expression levels of other HER family members. To determine the role of HER3 in CYLD regulation, the researchers assessed CYLD expression levels in HER3-overexpressing ovarian cancer cells. The results showed that CYLD expression was significantly reduced in HER3-overexpressing OVCAR3/A2780 cells (Figure 1B). Furthermore, compared to control cells, CYLD expression was increased in HER3-knockdown OVCAR3/A2780 cells (Figure 1C). These results further indicate that HER3 has a negative regulatory effect on CYLD expression. To further investigate how HER3 reduces CYLD expression, they examined the activation levels of several important regulatory proteins in HER3-overexpressing cells. The results showed that the level of the key intermediate signaling molecule p-STAT3 (T705) was significantly increased compared with control cells (Figure 1D), while the levels of other possible molecules, such as p-c-Jun, p-p38, and p-Erk1/2, did not change significantly. Furthermore, the expression level of p-STAT3 was also significantly reduced in HER3-silenced OVCAR3/A2780 cells (Figure 1D). Knockdown of STAT3 in A2780 and OVCAR3 cells or treatment with the STAT3 inhibitor STAT3-IN-1 induced CYLD expression. In addition, immunoprecipitation experiments indicated that HER3 may directly bind to and interact with CYLD (Figure 1E). Therefore, these results suggest that HER3 reduces CYLD expression levels by activating the STAT3 signaling pathway.

Figure 1. HER3 inhibited CYLD expression via phosphorylation of STAT3. (Zhang Y, et al., 2025)