Li-Chun Liu

Mitochondrial Dysfunction Involved in the Cytotoxicity of Tramadol in Human Endometrial Carcinoma Cells

Tramadol is a common anesthetic used to treat cancer pain, including endometrial cancer, but its function in endometrial cancer remains unclear. The purpose of this study was to elucidate the antitumor effects of tramadol on human endometrial cancer cells. Colony formation, BrdU, cell cycle profiles, apoptosis, ROS, and Western blot analyses were used to study the response of endometrial cancer cells to tramadol. JC-1 and seahorse metabolic flux assays were used to detect the effect of tramadol on mitochondria in endometrial cancer cells. Combination index was used to detect the interaction of tramadol with chemotherapy drugs in endometrial cancer cells. In this study, we found that tramadol was able to inhibit proliferation and induce cell cycle arrest, ROS generation, and apoptosis in two types of endometrial cancer cells. In addition, tramadol treatment also induced mitochondrial dysfunction in endometrial cancer cells by causing a loss of mitochondrial membrane potential and a decreased oxygen consumption rate. More importantly, the synergetic effect of tramadol with doxorubicin or cisplatin was further confirmed in endometrial cancer cells by the results of the combination index and apoptosis assay. In summary, our findings indicate that tramadol has an antitumor effect on endometrial cancer cells, which might serve as a potential adjuvant therapy strategy for endometrial cancer.

The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients’ survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

Dysregulated Immunological Functionome and Dysfunctional Metabolic Pathway Recognized for the Pathogenesis of Borderline Ovarian Tumors by Integrative Polygenic Analytics

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.