New pathogenic mechanism and potential treatment of oral cancer

Oral cancer is one of the leading cause of cancer deaths in Taiwan, prevalently occurring in the male population. However, its biological mechanisms and specific therapeutic strategies remain to be explored. MRE11 is the core component of the RAD50/MRE11/NBS1 complex for repair of DNA double-strand-breaks, and has been known as a critical factor in solid tumor development through its nuclease-dependent activity. In this article, we found a novel role of MRE11 in oral cancer progression by its nuclease-independent function, and delineated its key downstream signaling through the chemoattractant receptor CXCR4 as follows. First, MRE11 expression in oral cancer samples was positively associated with the tumor size, cancer stage, and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. In addition, MRE11 promoted oral cancer cell proliferation and migration/invasion ability, and the cancer-promoting effects of MRE11 were mediated by enhancing CXCR4 expression and its signaling. Notably, these phenomena were mitigated by using CXCR4 neutralizing antibodies in both in vitro and in vivo models. Moreover, inhibition of the nuclease-dependent activity of MRE11 by mirin reduced DNA repair of oral cancer cells; however, mirin treatment did not affect MRE11-promoted oral cancer cell proliferation and migration/invasion ability as described above, indicating that the nuclease-independent function of MRE11 underlies these pro-cancer effects. Collectively, MRE11 may serve as a clinical indicator and therapeutic target in oral cancer, displaying dual nuclease-dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment. These findings will also facilitate future development of personalized medicine according to the differential expression of MRE11 in oral cancer patients.

Graphical Abstract:

Application and Highlights:

§   High expression level of MRE11 in oral cancer tissues is associated with adverse oral cancer progression and treatment outcomes by radiotherapy

§   MRE11 promotes oral cancer cell proliferation and migration/invasion ability through upregulation of chemoattractant receptor CXCR4 and its signaling

§   These cancer-promoting effects result from the nuclease-independent function of MRE11

§   MRE11 may have clinical benefits as a prognostic indicator and novel target for oral cancer treatment

Research Team Members:

Associate Professor Yen-Yun Wang and Professor Shyng-Shiou F. Yuan are dedicated to the translational research of the etiology, pathogenesis, treatment and prevention of oral cancer. Team members including Yen-Yun Wang, Yuk-Kwan Chen, Steven Lo, Tsung-Chen Chi, Yi-Hua Chen, Stephen Chu-Sung Hu, Ya-Wen Chen, Shih Sheng Jiang, Fang-Yu Tsai, Wangta Liu, Ruei-Nian Li, Ya-Ching Hsieh, Chih-Jen Huang & Shyng-Shiou F. Yuan

Representative Department:

Associate Professor Yen-Yun Wang:

School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Professor Shyng-Shiou F. Yuan:

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University

Introduction of Research Team:

The first author Yen-Yun Wang is a full-time associate professor in the School of Dentistry, Kaohsiung Medical University, and an appointed member of the Center for Cancer Research, Kaohsiung Medical University and Translational Research Center, Kaohsiung Medical University Hospital.

The corresponding author Shyng-Shiou F. Yuan is a full-time professor in the Graduate Institute of Medicine, Kaohsiung Medical University, and an appointed member of the Center for Cancer Research, Kaohsiung Medical University and Translational Research Center, Kaohsiung Medical University Hospital.

Contact Email:

Associate Professor Yen-Yun Wang: wyy@kmu.edu.tw

Professor Shyng-Shiou F. Yuan: yuanssf@kmu.edu.tw

Publication: Oncogene. 2021, 40: 3510–3532.

Full-Text Article: https://www.nature.com/articles/s41388-021-01698-5

Development of Fast Fluorescent Genotyping Platform for Detection of Nucleotide Variants in Human Genes.

In recent years, the public has begun to attach importance to health and preventive medicine, which has made genetic testing become a national development theme and academic research project. Since the completion of the Human Genome Project in 2000, more and more gene functions have been successfully interpreted, and more than 2,000 gene-related diseases have been discovered. Today, more than 700 gene-related diseases have been developed with corresponding drugs, treatments, cancer and many rare diseases. Genetic testing is to detect whether the mutation sites of the DNA sequence in the chromosome structure or the degree of gene expression, which provides the information for medical researchers to evaluate some diseases, physiques or personal characteristics related to genetic inheritance. Genetic testing is also a part of the precision medicine. Everyone's DNA genes are unique and personalized information, which causes everyone's innate physique, health status, and characteristics. In 2008, the American Time magazine selected this revolutionary technology as the top innovation of 2008.

  The current genetic testing technology often requires the use of some expensive consumables or large-scale instruments, which makes the testing cost high, and takes several days to several weeks. Therefore, not all laboratories can complete the testing technology. In order to make the gene detection technology simpler, more convenient, accurate and fast. This research has developed a technique for rapid application of fluorescence in gene mutation detection, which is applied to analyze survival motor neuron gene (SMN) for diagnosis of spinal muscular atrophy (SMA).

  SMA is a congenital genetic disease that causes muscle weakness and atrophy in patients. People with mild disease have inconvenience in mobility, and those with severe disease will die due to respiratory failure. The SMN gene that controls this disease has been known. Diagnosing this gene in the early stages of pregnancy can prevent the disease from occurring 96% or provide immediate treatment. Therefore, this gene testing is one of the genetic items that must be tested for pregnant women. So far, there are several clinical methods for diagnosing this gene, including restriction enzyme digestion (RFLP), real-time PCR, denatured HPLC (DHPLC), capillary electrophoresis, mass spectrometry or multiplex ligation-dependent probe amplification (MLPA), etc., but these methods are just like the aforementioned traditional genetic analysis methods. These analyses are time-consuming and require some expensive consumables or large instruments. In order to make gene detection simpler and faster, this study designed a fast fluorescent gene detection platform. The principle is as shown in the summary. Only the primer pair needs to modify with the biotin group and the fluorescent group, respectively. This gene amplification was captured with magnetic beads, and finally cut with restriction enzymes. The fluorescent intensity changes can be used to understand the genotype of the survival motor neuron gene. This method is convenient, simple and fast, and the method is universal. As long as the appropriate restriction enzyme is selected, it can be applied to the detection of different genes, and it is quite suitable for the analysis of various types of gene mutations.

Graphical Abstract

Application and Highlights:

1. Genetic testing is to detect whether the mutation sites of the DNA sequence in the chromosome structure or the degree of gene expression, which provides the information for medical researchers to evaluate some diseases, physiques or personal characteristics related to genetic inheritance. Genetic testing is also a part of the precision medicine. 

2. In order to make the genetic testing technology simple, convenient, accurate and fast, this research develops a fast fluorescent detection technology in the analysis of gene mutations for determination of survival motor neuron gene (SMN) to diagnose spinal muscular atrophy (SMA).

3. This method is convenient, simple, fast, and versatile. It can be applied to the detection of different genes as long as the appropriate restriction enzymes are selected, and it is quite suitable for the analysis of various types of gene mutations.

Research Team Members:

Chun-Chi Wang, Chung-An Chen, Yuh-Jyh Jong, Hwang-Shang Kou 

Representative Department:

School of Pharmacy, College of Pharmacy, Kaohsiung Medical University

Introduction of Research Team:

The team has been committed to capillary electrophoresis, pharmaceutical analysis, genetic analysis, special probe and primer design, nanoparticle synthesis and application, etc. for many years. They have developed a number of technologies for drug monitoring or genetic testing, and obtained a number of patents.

Contact Email: chunchi0716@kmu.edu.tw

Publication: Analytical Chemistry 2018, 90(19): 11599–11606.

Full-TextArticle: https://pubs.acs.org/doi/10.1021/acs.analchem.8b02996