Release date: 2017-08-24
Mutations that help immortalize cells are critical for tumorigenesis, but in a new study, researchers from research institutions at the University of California, Berkeley, point out that cells become immortalized far more than originally thought. To be complicated. The relevant research results were published online in the journal Science on August 17, 2017, entitled "Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism".
The key to cell immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. This enzyme extends the telomeres at the ends of the chromosome, and these telomeres become shorter during each cell division.
When the telomeres are too short, the ends of the chromosomes are linked to each other, which causes damage when the cells divide, and in most cases kills the cells.
Given that telomeres become shorter as cells age, scientists have theoretically believed that cancer cells that are never senescent become immortalized by producing telomerase that cells do not normally produce, and thus These cells permanently retain longer telomeres. It is estimated that 90% of malignant tumors use telomerase to achieve immortalization, and various cancer therapies proposed focus on reducing the production of telomerase in tumors.
In this new study, the researchers studied the immortalization process using in vitro cultured genomic engineering cells, and when skin cells progressed from sputum to malignant melanoma, they were also tracked, suggesting telomeres. Enzymes play a more complex role in cancer.
Dirk Hockemeyer, author of the paper and assistant professor of molecular and cell biology at the University of California, Berkeley, said: "Our findings have implications for how to consider the earliest processes that promote cancer production and the use of telomerase as a therapeutic target. The role of granulocyte biology in the early stages of cancer development has been greatly neglected. Our findings in melanoma are likely to be suitable for other cancer types, which means that people will study the earlier telomeres more carefully. Shortening the role played by a tumor suppressor mechanism."
From sputum to cancer
Hockemeyer, his colleagues at the University of California at Berkeley, and Boris Bastian, a dermatologist at the University of California, San Francisco, and colleagues found that cell immortalization is a two-step process that was initially caused by a mutation in activated telomerase, but this The activation level is lower. This mutation is located in a promoter upstream of the telomerase gene (referred to as TERT), which regulates the expression level of telomerase. Four years ago, it has been reported that approximately 70% of malignant melanomas have this same mutation in the TERT promoter.
Hockemeyer said that this TERT promoter mutation does not produce enough end-telomerase to immortalize the pre-cancerous cells, but it delays normal cell senescence, allowing more time for more activation of telomerase. Change happens. He suspects that telomerase levels are sufficient to extend the shortest telomeres, but not to allow them to have longer lengths and stay healthy.
If cells fail to increase telomerase expression, they are not immortalized and eventually die due to telomere shortening because the chromosomes are linked together and break down when the cell divides. Cells with this TERT promoter mutation are more likely to upregulate telomerase, which allows them to continue to grow despite very short telomeres.
However, Hockemeyer said that telomerase levels are lower, with the result that some unprotected chromosome ends appear in surviving mutant cells, which may lead to mutations and further promote tumor formation.
Hockemeyer said, "Before the publication of our paper, one might think that only obtaining this mutation in the TERT promoter is enough to immortalize the cell, and when this happens at any time, telomere shortening is eliminated. It was confirmed that this TERT promoter mutation was not immediately sufficient to prevent telomere shortening."
However, it remains unclear what ultimately leads to up-regulation of telomerase, resulting in immortalization of cells. Hockemeyer says it can't be another mutation, but an epigenetic change that affects telomerase gene expression, or a change in transcription factor or other regulatory protein that binds to the upstream promoter of the telomerase gene.
"However, we have evidence that the second step must occur and occurs when the length of the telomere is shortened to a critical value, at which point the telomere is malfunctioning and causes genomic instability."
In retrospect, this is not surprising.
Although most cancers appear to require telomerase to become immortalized, it is known that only about 10% to 20% of cancers undergo single nucleotide changes in the promoter upstream of the telomerase gene. However, this includes approximately 70% of melanoma and 50% of liver and bladder cancer.
Hockemeyer said that the evidence used to support the up-regulation of telomerase expression by this TERT promoter mutation has been paradoxical: cancer cells tend to have shorter telomere chromosomes but higher levels of telomerase, which A high level should produce longer telomeres.
According to these new findings, telomeres are relatively short in precancerous cells because telomerase is just sufficient to maintain without prolonging telomeres.
Hockemeyer said, "Our paper reconciles conflicting information about cancers that carry this mutation."
The discovery also addresses another recent counterintuitive finding: people with shorter telomeres are more resistant to melanoma. The reason, he said, is that if a TERT promoter mutation promotes the conversion of precancerous lesions (黑色) to melanoma, then in people with shorter telomeres, telomerase is expressed on the cells and they become These cells will die before immortalization.
The study also involved genetic engineering of cells differentiated from human pluripotent stem cells to carry TERT promoter mutations, followed by a progression of their immortalization. These results are identical to those observed in human skin lesion samples obtained from patients at the University of California, San Francisco, at the Helendale Family Comprehensive Cancer Center.
Source: Bio Valley (WeChat: BIOONNEWS)
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