Cancers: Melatonin inhibits DNA repair and enhances chemosensitivity of liver cancer through LncRNA

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Introduction to the background of the article

BACKGROUND INTRODUCTION

Liver cancer (HCC) is one of the most refractory malignancies, especially when it progresses to advanced stages and surgical resection is no longer feasible. Chemotherapy is basically the only option available to these patients. Etoposide (VP16) and camptothecin (CPT) are clinically used chemotherapeutic drugs that induce DNA damage in cancer cells and cause apoptosis. However, due to the accumulation of mutations, the DNA repair system in most HCC cells is abnormally active and the DNA repair ability is improved, resulting in poor chemotherapy. Recent studies have shown that when DNA repair pathways in cancer cells are blocked, the effects of chemotherapy and radiotherapy can be significantly enhanced. Therefore, some DNA repair blockers have been widely used in clinical treatment, and these drugs can reduce chemotherapy. The dose of the drug increases the therapeutic effect.

DNA damage repair is an important mechanism to maintain chromosomal stability. Protein dysregulation during DNA repair increases the possibility of DNA mutation and can lead to cell death or carcinogenesis. DNA repair mechanisms can be subdivided into two broad categories: double-strand break repair (DSBR) and single-strand break repair (SSBR). Homologous recombination (HR) is the main mechanism of DSBR, and RAD51 is a key protein involved in this process. RAD51 protein binds to single-stranded DNA to facilitate HR to complete DNA repair, and inhibition of RAD51 expression strongly impedes DNA repair. Therefore, many RAD51 inhibitors have been identified as adjuvant therapies for HCC therapy and have been shown to enhance the efficacy of chemotherapy and radiation therapy.

Melatonin is the main hormone secreted by the pineal gland in the human brain. In addition to regulating the sleep-wake cycle, melatonin and its metabolites are still strong free radical scavengers, which can reduce the damage caused by peroxides produced by physiological metabolism. In addition, melatonin activates immunity, inhibits angiogenesis and cell growth, and inhibits the metastasis of several cancers. Although recent studies have reported that melatonin can inhibit the growth and metastasis of hepatoma cell lines, the results of the study are limited to cell experiments, and the downstream regulation mechanism is still unclear.

2018, Chin-Chuan Chen Chang Gung University in Taiwan and other people "Cancers" (IF = 5.326, Medical Area 2) published a report entitled "Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1- Mediated Suppression of DNA Repair" article.

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Main method used

METHODS

1. Comet assay: Also known as single-cell gel electrophoresis, it was first proposed by Ostell in 1984 to identify genotoxicity by detecting DNA strand damage.

2. Immunofluorescence

3. HR analysis

4. Whole transcriptome sequencing

5. Mouse xenograft experiment

6. Immunohistochemical staining

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Summary of the main contents of the article

ABSTRACT

The DNA repair system of most liver cancer (HCC) cells is abnormally active due to cumulative mutations, and DNA repair ability is increased, resulting in resistance to chemotherapy and radiotherapy. Therefore, targeting DNA repair mechanisms is a common treatment in HCC, which can enhance the sensitivity of cancer cells to DNA damage. In this study, the authors analyzed the anti-HCC effects of melatonin and elucidated its regulatory mechanisms. Functional analysis showed that melatonin inhibited the proliferation, migration and invasion of HCC cells, and inhibited the DNA repair ability, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole transcriptome and functional gain and loss analysis showed that melatonin induced the expression of long-chain non-coding RNA (LncRNA) RAD51-AS1, which binds to RAD51 mRNA and inhibits its translation, thereby effectively reducing DNA repair in HCC cells. Ability to increase sensitivity to chemotherapy and radiation therapy. Animal models further demonstrate that the combination of melatonin and the chemotherapeutic drug etoposide (VP16) significantly inhibits tumor growth compared to monotherapy. Our results suggest that melatonin is a potential adjunct to HCC chemotherapy and radiation therapy.


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