New Nucleic Acids: Let the tumor suppressor genes no longer "silent"

New Nucleic Acids: Let the tumor suppressor genes no longer "silent"

September 4, 2018 Source: Science and Technology Daily

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In response to malignant tumors, nucleic acid drugs have received more and more attention in recent years due to their good targeting and therapeutic effects. Scientists are still trying to find new targeted drugs and research directions, awakening the body's own immune function when dealing with tumors, so that the tumor suppressor gene will no longer be a "silent lamb." Professor Yang Cheng from the School of Pharmacy of Nankai University studied the phenomenon of co-silencing of tumor suppressor genes in the malignant progression of tumors. Based on this phenomenon, artificial single-stranded circular DNA carried by nanospheres was designed to enhance the body's tumor suppression by adsorbing miRNAs. The level of expression of the gene, thereby inhibiting tumor progression. The cover article of the internationally renowned academic journal published in August this year and the American Cancer Society's journal Cancer Research reported the research results of Professor Yang Cheng's research group.

Breaking "common silence" helps to suppress cancer

Recently, Yang Cheng said in an interview with the Science and Technology Daily reporter that tumor patients often have low expression of tumor suppressor genes in tumor cells. In tumors, a common phenomenon in which a variety of tumor suppressor genes are silenced leads to an increase in tumor malignancy. Traditional anti-tumor drugs mostly target a single oncogene rather than a tumor suppressor, and in particular, there are few anti-tumor drugs that can simultaneously target multiple tumor suppressor genes. Therefore, "If you can activate the tumor suppressor genes and fully mobilize their enthusiasm, it may be another kind of scene to deal with the tumor." Yang Cheng said.

What is the total gene silencing? Yang Cheng explained that gene silencing means that the gene present in the organism is not lost or damaged, but the gene does not express or express very low levels. "Like human beings, many genes don't 'speak', that is, the phenomenon of total gene silencing, such silence is terrible when dealing with tumors," Yang Cheng said.

The reporter learned that gene silencing is an important means of gene expression regulation in eukaryotic cells and a hotspot in biomedical research.

Previous studies have found that three tumor suppressor genes, KLF17, CDH1 and LASS2, are underexpressed in a variety of tumors, and the co-silencing of tumor suppressor genes is strongly correlated with the survival of tumor patients. Studies have now confirmed that abnormal regulation of miRNAs is also strongly associated with malignant tumors, and many miRNAs often regulate multiple target genes.

Yang Cheng stressed that regulating the level of miRNA in cells may release the tumor suppressor gene at the same time, breaking its co-silencing, and may become a more effective tumor treatment in the future. The study found that miRNA-9 in tumors can simultaneously inhibit the expression of three tumor suppressor genes KLF17, CDH1 and LASS2. Therefore, scientists are working hard to find ways to reduce the level of miRNA-9 in cancer cells, thereby eliminating the co-silencing of tumor suppressor genes, increasing the expression level of suppressor genes in patients, and effectively resisting tumors.

New circular DNA into "adsorption" sponge

Yang Cheng told reporters that they designed a special single-stranded circular DNA (CSSD), which is a type of covalently closed DNA. The circular DNA is designed to mimic circular RNA (circRNA) in the body, which is highly conserved in evolution and more stable than linear RNA. "Recent studies have found that some circRNAs contain miRNA binding sites that can act as miRNA 'sponge' to adsorb miRNAs. We designed circular RNAs rich in miRNA binding sites to mimic circRNA properties to further enhance its stability in humans. Sex, let it adsorb miRNA-9 and inhibit its function."

Yang Cheng said that their team designed a variety of CSSD, one of which consists of artificial circular single-stranded DNA (CSSD-9) with multiple miRNA-9 adsorption sites, which has good stability and resistance to degradation.

The experimental results also verified the original idea. The results showed that CSSD can break the common "silence" phenomenon of the "three brothers" by adsorbing oncogenic miRNA-9 and releasing the tumor suppressor genes -KLF17, CDH1 and LASS2. These tumor suppressor genes have increased viability and increased expression in cancer cells. Thus, tumor progression and metastasis are effectively inhibited. The results show that in the tumors with high miRNA-9 content such as liver cancer, breast cancer, lung cancer, ovarian cancer and cervical cancer, this new circular DNA drug has obvious adsorption effect, which can fully mobilize the positivity and initiative of tumor suppressor genes. Sex.

New target drug prospects

Yang Cheng told reporters that in vitro and in vivo experiments, they found that the artificial single-stranded circular DNA developed by them has no obvious toxic effects on normal cells and various organs of mice, and has a certain enhancement to mouse immunity. Therefore, this study proposes a new and stable and effective miRNA inhibitor, CSSD, to release tandem "co-silencing" tumor suppressor genes. "From the perspective of adsorbing miRNAs to release co-silencing tumor suppressor genes, our research may provide a multi-target potential anti-tumor drug for tumor therapy." Yang Cheng said with a little excitement: "Although the road ahead is still long, but finally Take the first step."

The reporter learned that Yang Cheng's research and development direction is mainly aimed at the molecular mechanism of epigenetic regulation of malignant tumor metastasis and the development of non-coding nucleic acid drugs. Previously, the anti-tumor target PAR1 of doxycycline “new drug use”, which was first reported in the world, is the research result of the Yang Cheng team. Today, this study has entered Phase I-II clinical trials as a new targeted drug.

“All roads lead to Rome, and each target is worth a million dollars.” In the field of bio-targeted drug research and development, there has been a saying that every drug development target may be one billion billion dollars. The heavy products may also eventually be invested and huge. This time, Yang Cheng and his team undoubtedly opened a new door to fight cancer. (Sun Yusong)

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