The most common type of liver cancer, hepatocellular carcinoma (HCC), is the third leading cause of cancer-related death worldwide, and thus its incidence is rising sharply, both in the United States and worldwide. Although chemotherapy, surgery, and a liver transplant may cure some patients, more targeted therapies for this cancer could save the lives of millions more.
Two clock genes, BMAL1 and CLOCK, are particularly implicated
in hepatocellular carcinoma (HCC) cell proliferation. The study shows that in humans, these HCC cells depend on BMAL1 and CLOCK to maintain sustained cell growth. Targeting these clock proteins could provide promising new therapeutic avenues against cancer.
De récentes études ont suggéré un lien indirect entre les protéines de l’horloge circadienne presentes à l’interieur des cellules et le development of cancer du foie, à partir d’observations in vitro et d’examens de cellules prelevées sur des patients atteints d ‘cancer. “However, these studies have not given us a clear picture of how to target the processes within HCC cells,” adds lead author Dr. Steve A.K., professor of neuroscience and biomedical engineering and biology at the Keck School.
studying It consists of a series of experiments, in vitro on cell cultures, genetic analysis and in vivo, on animal models. The researchers showed that:
- Two major CLOCK proteins, called CLOCK and BMAL1, are required for HCC cell replication in cell culture;
- When CLOCK and BMAL1 are deleted, the proliferation process of cancer cells stops, which leads to apoptosis of cancer cells. Triggering apoptosis, during which a cell stops dividing and then self-destructs, is the goal of many modern cancer therapies;
- Genetic analysis of tumor cells reveals that knockdown of clock proteins reduces Wee1 enzyme levels and increases p21 reductase levels: thus, p21 is identified as a repressor and Wee1 as an accelerator of tumor proliferation. And so those are two new goals that have just been set;
- An in vivo study of murine models of liver cancer revealed that transplantation of cells modified to suppress CLOCK and BMAL1 significantly reduces tumor growth.
So not only does the study link clock proteins to liver cancer,
But it also illustrates precisely how cancer cells hijack the circadian clock to divide and metastasize. At the same time, this work indicates that inhibition of clock proteins can prevent cancer cells from reproducing.
So it is a new innovative strategy that has been proposed to us, which targets the biological clock, both in cancer cells, but also in the tumor microenvironment, which can help improve the efficacy of other standard therapies.
It “remains,” the researchers write, in order to better decipher the relationship between circadian proteins Wee1 and the p53 gene.