摘要：
PURPOSE: To explore the relationship between Mycoplasma hyorhinis infection and tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients. METHODS: Mycoplasma hyorhinis infection can be verified with the monoclonal antibody PD4, which specifically recognizes a distinct protein of M. hyorhinis. Immunohistochemistry (IHC), using PD4 to detect M. hyorhinis, was performed on paraffin-embedded lung adenocarcinoma tissues of patients who had epidermal growth factor (EGFR) mutations and had received oral TKI. The number of patients enrolled in our study was 101. Assessments following TKI treatment were performed until objective disease progression or stable disease at the cutoff date was reached. In all of the patients, the primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Immunohistochemistry revealed that 61 of 101 cases (60.4%) of lung adenocarcinoma were positive for M. hyorhinis, which comprised of 31 low-positive cases and 30 high-positive cases; the remaining 40 cases (39.6%) were negative. The median PFS was significantly longer in the negative group [18months (95% CI 14.15-21.85)] than in the low-positive group [10months (95% CI 7.70-12.30); hazard ratio (HR) 4.095, 95% CI 2.254-7.438; p < 0.001] and in the high-positive group [4months (95% CI 2.85-5.15); HR 31.703, 95% CI 14.425-69.678; p < 0.001]. The results of the subgroup analysis were satisfactory. The PFS benefit with negative M. hyorhinis infection was consistent across subgroups. CONCLUSIONS: In this retrospective, exploratory analysis, M. hyorhinis infection significantly reduced PFS. With increased levels of M. hyorhinis infection, the progression of the disease was more advanced, likely due to the hydrolysis of TKI by M. hyorhinis. A strong correlation was found between M. hyorhinis infection and TKI resistance in lung adenocarcinoma. This study provides potent evidence that M. hyorhinis hydrolyses TKI and will assist in the research of related mechanisms in the future. IMPLICATIONS FOR CANCER SURVIVORS: It provides an option to improve the efficacy of TKI, including strategies to decrease M. hyorhinis infection, thereby reducing long-term distress in TKI resistance patients with EGFR mutations.
期刊：
LETTERS IN DRUG DESIGN & DISCOVERY,2020年17(7):884-890 ISSN：1570-1808
通讯作者：
Liu, Wenbin;Du, Runlei;Cao, Rihui
作者机构：
[Jia, Yifan] Wuhan Univ, Dept Pain Management, Renmin Hosp, Wuhan 430060, Peoples R China.;[Liu, Wenbin] Wuhan Polytech Univ, Coll Hlth Sci & Nursing, Wuhan 430023, Peoples R China.;[Zhang, Xiaodong; Yu, Difei; Du, Runlei] Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China.;[Huang, Qiuhua; Cao, Rihui; Qiu, Liqin] Sun Yat Sen Univ, Sch Chem, Guangzhou 510275, Peoples R China.
通讯机构：
[Liu, Wenbin; Du, Runlei] W;[Cao, Rihui] S;Wuhan Polytech Univ, Coll Hlth Sci & Nursing, Wuhan 430023, Peoples R China.;Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China.;Sun Yat Sen Univ, Sch Chem, Guangzhou 510275, Peoples R China.
关键词：
Synthesis;quinolone;antiproliferative;autophagy;mechanism of action;ATG5 protein.
摘要：
Background: Quinolines have been characterized as a class of potential antitumor agents, and a large number of natural and synthetic quinolines acting as antitumor agents were reported. Methods: A series of 7-chloro-4(1H)-quinolone derivatives were synthesized. The antiproliferative effect of these compounds was evaluated by MTT assay against five human tumor cell lines. The mechanism of action of the selected compound 7h was also investigated. Results and Discussion: Most of the compounds had more potent antiproliferative activities than the lead compound 7-chloro-4(1H)-quinolone 6b. Compound 7h was found to be the most potent antiproliferative agent against human tumor cell lines. Further investigation demonstrated that compound 7h triggered ATG5-dependent autophagy of colorectal cancer cells by promoting the functions of LC3 proteins. Conclusion: These results were useful for designing and discovering more potent novel antitumor agents endowed with better pharmacological profiles.
摘要：
Mycoplasmas are a group of microbes that can cause human diseases. The mycoplasmal lipoprotein p37 promotes cancer metastasis, at least in part, by interacting with EGFR. In this study, we show that the p37 lipoprotein binds another member of the EGFR family, HER2, through the HER2 extracellular domain. The binding of p37-HER2 promotes phosphorylation of HER2 and activates the downstream signaling molecule Erk1/2. Because the HER2 signaling pathway contributes to breast tumor metastasis, our results imply that the mycoplasmal lipoprotein p37 may also be involved in breast cancer metastasis. This study contributes to our understanding of mycoplasmal lipoprotein p37 function and its potential involvement in tumorigenesis. (C) 2016 Published by Elsevier GmbH.
作者机构：
[Li, Shang-Ze; Liu, Yi; Zhang, Xiao-Dong; Zhang, Hui-Hui; Song, Yang; Du, Run-Lei; Jin, Bing-Xue] Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China.;[Liu, Wen-Bin] Wuhan Polytech Univ, Coll Hlth Sci & Nursing, Wuhan 430023, Peoples R China.
通讯机构：
[Zhang, Xiao-Dong] W;Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China.
摘要：
Cyclins are essential for cell proliferation, the cell cycle and tumorigenesis in all eukaryotes. UbcH10 regulates the degradation of cyclins in a ubiquitin-dependent manner. Here, we report that UbcH10 is likely involved in tumorigenesis. We found that cancer cells exposed to n-acetyl-leu-leu-norleucinal (ALLN) treatment and UbcH10 depletion exhibit a synergistic therapeutic effect. Abundant expression of UbcH10 drives resistance to ALLN-induced cell death, while cells deficient in UbcH10 were susceptible to ALLN-induced cell death. The depletion of UbcH10 hindered tumorigenesis both in vitro and in vivo, as assessed by colony formation, growth curve, soft agar and xenograft assays. These phenotypes were efficiently rescued through the introduction of recombinant UbcH10. In the UbcH10-deficient cells, alterations in the expression of cyclins led to cell cycle changes and subsequently decreases in tumorigenesis. The tumorigenesis of xenograft tumors from UbcH10-deficient cells treated with ALLN was decreased relative to wild-type cells treated with ALLN in nude mice. On the molecular level, we observed that UbcH10 deficiency enhances the activation of caspase 8 and caspase 3 but not caspase 9 to impair cell viability upon ALLN treatment. Collectively, our results suggest that, as an oncogene, UbcH10 is a potential drug target for the treatment of colorectal cancer.
