Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, second only to lung cancer and gastric cancer in terms of severity. This malignant tumor originates in the liver and often occurs due to chronic hepatitis virus infection (especially hepatitis B virus). Once diagnosed, patients are often in the advanced stage of the disease. Currently, the 5-year survival rate of patients is less than 50%. In recent years, with the rise of immunotherapy, scientists have gradually realized the key role of the tumor microenvironment (TME) in cancer development, but the immune escape mechanism of HCC is still complex and not completely clear.
Recently, in a research report entitled "HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cells via the long noncoding RNA HDAC2-AS2" published in the international journal Nature Communications, scientists from the Institute of Biophysics, Chinese Academy of Sciences and other institutions revealed the mechanism of action of a new type of long noncoding RNA (lncRNA) - HDAC2-AS2 in HCC through research. The relevant research results have brought new hope for liver cancer treatment.
The tumor microenvironment is the "soil" on which tumor cells survive, which contains immune cells, extracellular matrix and various signaling molecules. In HCC, tumor cells can suppress the function of the immune system through complex mechanisms to achieve immune escape. Long noncoding RNA (lncRNA) is a class of RNA molecules that do not encode proteins. In recent years, it has been found that it is widely involved in the occurrence, development and immune escape of tumors. However, the specific mechanism of action of lncRNA in HCC is still unclear. For this reason, researchers have focused on this issue and tried to unlock the "code" of HCC immune escape. In the article, the researchers first screened a variety of HCC cell lines. They found that a lncRNA called HDAC2-AS2 was significantly upregulated after the activation of the TGF-β signaling pathway. TGF-β is an important cytokine that plays a key role in the occurrence and development of liver cancer. The researchers found that the high expression of HDAC2-AS2 is closely related to the poor prognosis of HCC patients, but has no direct effect on tumor cell proliferation. This phenomenon has aroused great interest among researchers, who speculate that HDAC2-AS2 may affect tumor progression through other mechanisms.
Figure 1. Working model.
Further experiments showed that HDAC2-AS2 can be secreted into the tumor microenvironment by tumor cells through extracellular vesicles (EVs). These EVs can transport HDAC2-AS2 to immune cells around the tumor like "express parcels". The researchers pointed out that the level of HDAC2-AS2 carried by EVs in the blood of HCC patients was significantly higher than that of healthy people, which suggests that HDAC2-AS2 may be used as a potential biomarker for early diagnosis.
Even more surprising is that HDAC2-AS2 binds to the CDK9 protein in the cells after entering the immune cells. CDK9 is a key cyclin-dependent kinase that plays a vital role in the activation and function of T cells. The binding of HDAC2-AS2 to CDK9 will cause a decrease in CDK9 protein levels, thereby causing CD8+ T cells (an important anti-tumor immune cell) to malfunction. It is mainly manifested as increased cell exhaustion and apoptosis, and significantly reduced anti-tumor activity. This research finding reveals the key role of HDAC2-AS2 in HCC immune escape.
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This article not only reveals the mechanism of action of HDAC2-AS2 in HCC, but also provides a new target for the precision treatment of liver cancer. The researchers found that HCC tumors with high expression of HDAC2-AS2 were more sensitive to PD-1 antibody treatment. PD-1 is an immune checkpoint protein whose inhibitors can restore the anti-tumor function of T cells. Therefore, HDAC2-AS2 may affect the effect of immunotherapy by regulating the function of T cells by affecting CDK9. In addition, the researchers also used single-cell RNA sequencing technology to analyze T cells in HCC patients receiving immune checkpoint blockade (ICB). The results showed that CDK9 enhanced the function of CD8+ T cells in ICB treatment, which further confirmed the importance of CDK9 in HCC immunotherapy.
In the future, as more research is carried out, researchers look forward to finding more ways to defeat liver cancer and give patients a new life.
Reference
- Gao Y, et al. HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2. Nature Communications, 2025, 16(1): 2055.