Biology subjects

Choi, M.-H.

Publications and source records attributed to Choi, M.-H..

3 recordsLinked to original sources

bioRxiv2022

Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

cancer biology↗

bioRxiv2020

Ultra-fast Prediction of Somatic Structural Variations by Reduced Read Mapping via Pan-Genome k-mer Sets

Genome rearrangements often result in copy number alterations of cancer-related genes and cause the formation of cancer-related fusion genes. Current structural variation (SV) callers, however, still produce massive numbers of false positives (FPs) and require high computational costs. Here, we introduce an ultra-fast and high-performing somatic SV detector, called ETCHING, that significantly reduces the mapping cost by filtering reads matched to pan-genome and normal k-mer sets. To reduce the number of FPs, ETCHING takes advantage of a Random Forest classifier that utilizes six breakend-related features. We systematically benchmarked ETCHING with other SV callers on reference SV materials, validated SV biomarkers, tumor and matched-normal whole genomes, and tumor-only targeted sequencing datasets. For all datasets, our SV caller was much faster ([≥]15X) than other tools without compromising performance or memory use. Our approach would provide not only the fastest method for largescale genome projects but also an accurate clinically practical means for real-time precision medicine.

bioinformatics↗

bioRxiv2018

Connexin 43 plays an important role in the transformation of human cholangiocytes upon stimulation with Clonochis sinensis excretory-secretory protein and N-nitrosodimethylamine

BackgroundClonorchis sinensis is a group I bio-carcinogen responsible for cholangiocarcinoma (CHCA) in humans. However, the mechanism by which C. sinensis promotes carcinogenesis is unclear.\n\nMethodologyUsing the human cholangiocyte line H69, we investigated cell proliferation and gap junction protein expression after stimulation with the hepatotoxin N-nitrosodimethylamine (NDMA) and/or excretory-secretory products (ESP) of C. sinensis, which induce inflammation. NDMA and ESP treatment increased proliferation by 146% and the proportion of cells in the G2/M phase by 37%. Moreover, the expression of the cell cycle protein E2F1 and the cell proliferation-related proteins Ki-67 and cytokeratin 19 increased in response to combined treatment with NDMA and ESP. The gap-junction proteins connexin (Cx) 43 and Cx26 also increased. In contrast, Cx32 expression decreased in cells treated with NDMA and ESP. Cox-2 was also upregulated. Silencing of Cx43 reduced cell proliferation and significantly suppressed Cx26 and Cox-2 expression.\n\nConclusionsThese results suggest that Cx43 is an important factor in CHCA induced by C. sinensis ESP and NDMA and further investigations targeting this pathway may allow prevention of this deadly disease.\n\nAuthor summaryClonorchis sinensis, a human fluke, resides in the liver of humans and is commonly found in the common bile duct and gall bladder. This parasite is the main cause of cholangiocarcinoma, also called bile duct cancer, in humans. Of note, the excretory-secretory products (ESP) of C. sinensis are known to cause inflammation in the biliary epithelium, which may ultimately result in neoplasms via production of reactive oxygen species and subsequent DNA damage. Together with N-nitrosodimethylamine (NDMA), a potent hepatotoxin that can cause fibrosis and tumors in the liver, ESP led to an increase in the growth and proliferation of cholangiocytes. Our results showed that the ESPs of C. sinensis induced pro-inflammatory responses by increasing the levels of proinflammatory cytokines and nuclear factor kappa B (NF{kappa}B), which in turn, enhanced the production of connexin 43 (Cx43), a gap-junction protein. Therefore, Cx 43 can serve as a potential target for developing a therapeutic strategy for the treatment of cholangiocarcinoma in humans.

cancer biology↗