LATS-regulated nuclear-cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial-mesenchymal transition

Abnormal cholesterol synthesis plays a crucial role in the development of hepatocellular carcinoma (HCC). Sterol regulatory element-binding protein 2 (SREBP2) is involved in cholesterol synthesis by translocating to the nucleus where it stimulates the transcription of genes encoding enzymes involved in the cholesterol synthesis pathway. However, the function and regulatory mechanism of SREBP2 in HCC remain unclear. In this study, we aimed to gain a better understanding of the effects of SREBP2 and its functional mechanism in HCC. In 20 HCC patients, we demonstrated that SREBP2 was highly expressed in HCC specimens, relative to their peritumoral tissue, and that higher expression correlated positively with a poor prognosis in these patients. Moreover, higher SREBP2 levels in the nucleus enhanced the occurrence of microvascular invasion, whereas inhibition of SREBP2 nuclear translocation by fatostatin markedly suppressed the migration and invasion of HCC cells via the epithelial-mesenchymal transition (EMT) process. The effects of SREBP2 were subject to functional activity of large tumor suppressor kinase (LATS), whereas inhibition of LATS promoted nuclear translocation of SREBP2, as observed in hepatoma cells and a subset of subcutaneous tumor samples from nude mice. In conclusion, SREBP2 enhances the invasion and metastasis of HCC cells by promoting EMT, which can be strengthened by the repression of LATS. Therefore, SREBP2 may serve as a novel therapeutic target for HCC.

 

Comments:

The provided text describes a study conducted to investigate the role of Sterol Regulatory Element-Binding Protein 2 (SREBP2) in hepatocellular carcinoma (HCC), a type of liver cancer. Here's a summary of the key findings and implications of the study:

1. SREBP2 Expression in HCC: The study found that SREBP2 was highly expressed in HCC tumor samples compared to adjacent non-tumor tissue in 20 HCC patients.

2. Prognostic Value of SREBP2: The higher expression of SREBP2 in HCC specimens was associated with a poor prognosis in these patients. This suggests that SREBP2 expression levels could potentially serve as a prognostic marker for HCC.

3. Microvascular Invasion: Increased levels of SREBP2 in the nucleus of HCC cells were correlated with a higher occurrence of microvascular invasion. Microvascular invasion refers to the spread of cancer cells into small blood vessels around the tumor, indicating an aggressive phenotype and poorer prognosis.

4. Inhibition of SREBP2: The researchers used a compound called fatostatin to inhibit the nuclear translocation of SREBP2. This inhibition resulted in the suppression of migration and invasion of HCC cells through a process called epithelial-mesenchymal transition (EMT). EMT is a cellular process that promotes cancer cell migration and invasion.

5. Role of Large Tumor Suppressor Kinase (LATS): The study found that the functional activity of Large Tumor Suppressor Kinase (LATS) influenced the effects of SREBP2. Inhibition of LATS promoted the nuclear translocation of SREBP2, suggesting that LATS may act as a regulator of SREBP2 function.

6. In Vivo Validation: The researchers observed similar results in hepatoma cells and a subset of subcutaneous tumor samples from nude mice, further supporting the role of SREBP2 in promoting HCC cell invasion and metastasis.

7. Therapeutic Implications: Based on the findings, the study suggests that SREBP2 could serve as a novel therapeutic target for HCC. By inhibiting SREBP2 or targeting its regulatory mechanisms, it may be possible to hinder the invasive and metastatic properties of HCC cells.

In summary, this study highlights the significance of SREBP2 in HCC progression and provides insights into its functional mechanism. By elucidating the relationship between SREBP2, LATS, and the EMT process, the study suggests that targeting SREBP2 could be a promising therapeutic strategy for HCC. However, further research is needed to validate these findings and explore the potential clinical applications of targeting SREBP2 in HCC treatment.

Related Products

Cat.No.	Product Name	Information
S8284	Fatostatin HBr	Fatostatin HBr is an inhibitor of sterol regulatory element binding protein (SREBP). It impairs the activation of SREBP-1 and SREBP-2.

Related Targets

SREBP Fatty Acid Synthase