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Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance

Background: This study aimed to investigate the possible role of inhibiting chromobox protein homologue 4 (CBX4) to deregulate of cancer stem cells (CSCs) and to evaluate the contribution of these molecules to sorafenib resistance in advanced hepatocellular carcinoma (HCC).

Methods: HCC cell lines and a xenograft mouse model with resistance to sorafenib were employed to analyse the effects of miR424 on CSC characteristics. RNA expression was analysed by RT-PCR and next-generation sequencing in a cohort of HCC cancer patients and sorafenib-resistant (SR) cell lines, respectively, to validate the key microRNAs and targets in the network.

Results: MicroRNA and mRNA profiles of SR cell lines identified miR424 and its direct target CBX4 as significantly associated with stem-cell-like properties, poor survival, and clinical characteristics. Functional experiments demonstrated that miR424 suppressed CBX4 and CBX4 induced nuclear translocation of YAP1 protein but was not associated with protein production. When YAP1 and CBX4 were modulated with CA3 and UNC3866, tumorigenicity and stem-like properties were extremely inhibited, thus indicating that these compounds exerted a strong anti-tumour effect in vivo against SR HCC cells.

Conclusions: Our results revealed that blocking CBX4 expression is critical in response to sorafenib resistance with advanced HCC.

 

Comments:

This study seems focused on understanding the mechanisms behind sorafenib resistance in advanced hepatocellular carcinoma (HCC) and the role of specific molecules like miR424 and CBX4 in cancer stem cell characteristics.

Here's a breakdown of the key findings and implications:

1. **Identification of miR424 and CBX4**: The study found that miR424 and its direct target CBX4 are associated with stem-cell-like properties in HCC, poorer survival rates, and clinical characteristics, especially in sorafenib-resistant (SR) cell lines.

2. **Functional Experiments**: The experiments revealed that miR424 suppressed CBX4 expression, leading to the nuclear translocation of the YAP1 protein. This modulation was associated with tumorigenicity and stem-like properties, indicating the potential role of these molecules in HCC progression and drug resistance.

3. **Therapeutic Potential**: Modulating YAP1 and CBX4 using compounds like CA3 and UNC3866 significantly inhibited tumorigenicity and stem-like properties in vivo, suggesting that these compounds could have potent anti-tumor effects against SR HCC cells.

4. **Conclusion**: The study concludes that blocking CBX4 expression is crucial in addressing sorafenib resistance in advanced HCC. This finding could potentially pave the way for developing targeted therapies or interventions aimed at inhibiting CBX4 to overcome drug resistance in HCC.

Overall, this research provides valuable insights into the molecular mechanisms underlying sorafenib resistance in HCC and highlights the potential therapeutic targets like CBX4 and miR424 that could be exploited to overcome drug resistance in advanced stages of this cancer.