International Business Department           Liu Bojia           October 09, 2023

  Liver cancer, one of the major cancers causing death threat to human beings all over the world, especially hepatocellular carcinoma (HCC) is the most common. In the past 20 years, the incidence of liver cancer has been rising globally. China is a truly big country for liver cancer, with more than 400,000 new cases of liver cancer in 2020, resulting in about 390,000 deaths, both close to half of the global rate.

  Recently, a new study was published in the top academic journal Cell, which is expected to provide a new approach to improving liver cancer diagnosis and treatment. Researchers from the University of Basel, Switzerland, looked at the metabolic characteristics of cancer cells and found arginine, a key amino acid that drives metabolic reprogramming in tumours.

  "Advances over the past decade have shown that cancer is a metabolic disorder disease," the researchers note in their paper, "and that several major metabolic pathways are rearranged in order to enhance the proliferative capacity of cells." For example, cancer cells consume much more glucose than normal cells, and they also have the ability to snatch and absorb nutrients.

  To further understand the metabolic changes in liver cancer cells, in the new study, the scientists launched a multifaceted analysis of tumour samples from liver cancer model mice and liver cancer patients in terms of untargeted metabolomics, transcriptomics, and proteomics. The results found that these tumour cells had high concentrations of arginine, even though the tumour cells themselves produced little or almost no of this amino acid.

  Arginine is a versatile amino acid that is not only one of the basic components of protein synthesis, but also a precursor of polyamines, creatine and nitric oxide. Further experiments have shown that tumour cells are able to maintain high levels of arginine by increasing uptake as well as decreasing conversion to polyamines.

  In mouse experiments, when researchers reduced the arginine level in their diets to 20% or even 8% of a normal diet, a significant reduction in tumour load was seen in the liver cancer model mice, suggesting that the amino acid is much needed for the development of liver tumours.

  So how do changes in arginine levels affect tumourigenicity? In this study, scientists revealed that high levels of arginine bind to specific factors that trigger tumour cells to reprogramme their metabolic processes. Arginine regulates the expression of metabolic genes by binding to RNA-binding motif protein 39 (RBM39), allowing tumour cells to divide indefinitely like embryonic cells.

  Not only that, but since arginine is also an amino acid that immune cells depend on for proper functioning, as arginine is depleted in a big way, it becomes easier for tumour cells to escape the control of the immune system, further promoting tumour growth.

  Since high levels of arginine drive metabolic reprogramming of cancer cells and promote tumour growth, researchers have thought of ways to contain tumours accordingly.

  Considering that immune cells also require arginine to function properly, it is clear that the overall level of arginine cannot be lowered without accidentally injuring normal cells. Therefore, the researchers' strategy was to target a specific molecule, RBM39, that binds to arginine in cancer cells. there is an anti-cancer drug, Indisulam, that is recruiting RBM39 and causing it to be degraded via ubiquitin, thus stopping the metabolic reprogramming of cancer cells.

  Using cells from 20 liver cancer patients, the researchers created organoid models and treated them with Indisulam. The results of the experiment showed that all 20 groups of organoids had their growth arrested by the drug in a dose-dependent manner.

  The paper concludes that this suggests that depletion of RBM39 might be a new option for treating hepatocellular carcinoma.

  In addition, metabolic changes such as elevated arginine levels could be used as biomarkers for early detection of cancer. The difficulty of treating liver cancer is very much related to the difficulty of diagnosing it, with most patients with hepatocellular carcinoma being diagnosed at an advanced stage due to a lack of clear early symptoms. If early detection can be improved, then it will also bring important positive effects to increase the success rate of treatment and improve the survival rate of patients. A new breakthrough in liver cancer diagnosis and treatment may not be far away.