ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

Wang, Lei,Wang, Qiu-Tong,Liu, Yu-Peng,Dong, Qing-Qing,Hu, Hai-Jie,Miao, Zhi,Li, Shuang,Liu, Yong,Zhou, Hao,Zhang, Tong-Cun,Ma, Wen-Jian,Luo, Xue-Gang The Korean Gastric Cancer Association 2017 Journal of gastric cancer Vol.17 No.4

Purpose: We previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined. Materials and Methods: SMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses. Results: Compared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells. Conclusions: To the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.

Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation Sequencing

Hai-Yun Wang,Ling Deng,Ying-Qing Li,Xiao Zhang,Ya-Kang Long,Xu Zhang,Yan-Fen Feng,Yuan He,Tao Tang,Xin-Hua Yang,Fang Wang 대한암학회 2021 Cancer Research and Treatment Vol.53 No.4

Purpose Current variability in methods for tumor mutational burden (TMB) estimation and reporting demonstrates the urgent need for a homogeneous TMB assessment approach. Here, we compared TMB distributions in different cancer types using two customized targeted panels commonly used in clinical practice. Materials and Methods TMB spectra of 295- and 1021-gene panels in multiple cancer types were compared using targeted next-generation sequencing (NGS). The TMB distributions across a diverse cohort of 2,332 cancer cases were then investigated for their associations with clinical features. Treatment response data were collected for 222 patients who received immune-checkpoint inhibitors (ICIs) and their homologous recombination DNA damage repair (HR-DDR) and programmed death-ligand 1 (PD-L1) expression were additionally assessed and compared with the TMB and response rate. Results The median TMB between gene panels was similar despite a wide range in TMB values. The highest TMB was eight and 10 in patients with squamous cell carcinoma and esophageal carcinoma according to the classification of histopathology and cancer types, respectively. Twenty-three out of 103 patients (22.3%) were HR-DDR–positive and could benefit from ICI therapy; out of those 23 patients, seven patients had high TMB (p=0.004). Additionally, PD-L1 expression was not associated with TMB or treatment response among patients receiving ICIs. Conclusion Targeted NGS assays demonstrated the ability to evaluate TMB in pan-cancer samples as a tool to predict response to ICIs. In addition, TMB integrated with HR-DDR–positive status could be a significant biomarker for predicting ICI response in patients.

SMYD3-associated pathway is involved in the anti-tumor effects of sulforaphane on gastric carcinoma cells

Qing-Qing Dong,Qiu-Tong Wang,Lei Wang,Ya-Xin Jiang,Mei-Ling Liu,Hai-Jie Hu,Yong Liu,Hao Zhou,Hong-Peng He,Tong-Cun Zhang,Xuegang Luo 한국식품과학회 2018 Food Science and Biotechnology Vol.27 No.4

Sulforaphane (SFN), a natural compound derived from cruciferous vegetables, has been proved to possess potent anti-cancer activity. SMYD3 is a histone methyltransferase which is closely related to the proliferation and migration of cancer cells. This study showed that SFN could dose-dependently induce cell cycle arrest, stimulate apoptosis, and inhibit proliferation and migration of gastric carcinoma cells. Accompanied with these anticancer effects, SMYD3 and its downstream genes, myosin regulatory light chain 9, and cysteine-rich angiogenic inducer 61, was downregulated by SFN. Furthermore, overexpression of SMYD3 via transfection could abolish the effects of SFN, suggesting that SMYD3 might be an important mediator of SFN. To the best of our knowledge, this is the first report describing the role of SMYD3 in the anti-cancer of SFN. These findings might throw light on the development of novel anti-cancer drugs and functional food using SFN-rich cruciferous vegetables.

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

Lei Wang,Qiu-Tong Wang,Yu-Peng Liu,Qing-Qing Dong,Hai-Jie Hu,Zhi Miao,Shuang Li,Yong Liu,Hao Zhou,Tong-Cun Zhang,Wen-Jian Ma,Xuegang Luo 대한위암학회 2017 Journal of gastric cancer Vol.17 No.4

Purpose: We previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined. Materials and Methods: SMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses. Results: Compared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells. Conclusions: To the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.

Clinical Study of Thalidomide Combined with Dexamethasone for the Treatment of Elderly Patients with Newly Diagnosed Multiple Myeloma

Chen, Hai-Fei,Li, Zheng-Yang,Tang, Jie-Qing,Shen, Hong-Shi,Cui, Qing-Ya,Ren, Yong-Ya,Qin, Long-Mei,Jin, Ling-Juan,Zhu, Jing-Jing,Wang, Jing,Ding, Jie,Wang, Ke-Yuan,Yu, Zi-Qiang,Wang, Zhao-Yue,Wu, Tian Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.9

Objective: To investigate the relationship between the efficacy and safety of different doses of thalidomide (Thal) plus dexamethasone (Dex) as the initial therapy in elderly patients with newly diagnosed multiple myeloma (MM). Methods: Clinical data of 28 elderly patients with newly diagnosed MM who underwent the TD regimen as the initial therapy were analyzed retrospectively. The patients were divided into two groups according to the maximal sustained dose of Thal: lower dose (group A) and higher dose (group B). The overall response rate (ORR), progression free survival (PFS), overall survival (OS), and adverse events (AES) were compared between the two groups. Results: A total of 28 patients were followed up with a median of 18 months. The ORR was 60.1%. The median response time and PFS were 2.0 and 17.0 months, respectively. The mean sustained dose of Thal in group B was significantly higher than group A (292.9 mg v 180.4 mg, P=0.01). There was no significantly difference in ORR (57.1% v 64.3%, P=1.00) and PFS (9.63months v 17.66 months, P=0.73) between groups A and B. During the follow up, only five patients died (<40%) and, therefore, median OS values were not available. It is estimated, however, that the mean survival time in the two groups was 35.6 and 33.4 months (P>0.05), respectively. All of the patients tolerated the treatment well. The incidence of AES in patients with a grading above 3 in group B was significantly higher than in group A (P=0.033). Conclusions: The TD regimen results in a high response rate and manageable AES as the initial therapy in elderly patients with MM. TD should be considered as the front line regimen for the treatment of elderly patients with MM in areas with financial constraints. The clinical response can be achieved at a low dose Thal with minimal toxicity.

Association between FGFRs and the susceptibility of digestive and reproductive system cancers in Chinese population

Jia-Kang Wang,Shu-jun Guo,Bao-qing Tian,Chnag-jun Nie,Hai-long Wang,Jia-lang Wang,An Hong,Xiao-jia Chen 대한독성 유전단백체 학회 2017 Molecular & cellular toxicology Vol.13 No.4

Fibroblast growth factors(FGFs) and their receptors (FGFRs) modulate a wide range of biological functions, especially tumor genesis. The aim of this study was to investigate the possible association of FGFR expression with the susceptibility of digestive system and reproductive system cancers in Chinese population. In total, 343 patients with digestive or reproductive system cancers were enrolled in this study. The expression levels of four highly-conserved FGFRs including FGFR1, FGFR2, FGFR3 and FGFR4 were measured by immunohistochemistry (IHC). The expression levels of FGFRs were compared between carcinoma and para-carcinoma tissues. FGFR1 expression significantly differed between carcinoma and para-carcinoma tissues in colon and gastric cancers. FGFR2 expression significantly differed between carcinoma and para-carcinoma tissues in esophageal cancer. FGFR3 expression was significantly different between carcinoma and para-carcinoma tissues in liver and gastric cancers. FGFR2 showed the highest expression probability in all the selected cancers and FGFR4 showed the lowest expression probability. FGFR1 and FGFR3 showed comparable moderate expression probabilities. Our findings have demonstrated significant differences regarding FGFR expression levels between carcinoma and para-carcinoma cells in digestive or reproductive system cancer patients. The data also implicated that FGFR2 and FGFR4 could serve as two prominent factors closely related to the susceptibility of digestive and reproductive system cancers.

Silencing of Twist Expression by RNA Interference Suppresses Epithelial-mesenchymal Transition, Invasion, and Metastasis of Ovarian Cancer

Wang, Wen-Shuang,Yang, Xing-Sheng,Xia, Min,Jiang, Hai-Yang,Hou, Jian-Qing Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.9

Purpose: This study aimed to explore the role of the Twist gene in the epithelial-mesenchymal transition of ovarian cancer. Methods: An RNA interference plasmid expressing a small interfering RNA (siRNA)-targeting Twist (Twist siRNA vector) was designed, constructed, and transfected into the human ovarian cancer cell line A2780. Transfection efficiency was assessed under a fluorescence microscope. Changes in the expression of Twist mRNA in A2780 after transfection with the pGenesil Twist shRNA plasmid were analyzed through RT-PCR. MTT assays and adhesion experiments were applied to determine changes in proliferation and adhesion ability of A2870 after transfection with the Twist shRNA plasmid. Changes in the expression of the E-cadherin and N-cadherin proteins in A2780 after transfection with the Twist shRNA plasmid were analyzed using Western blotting. Result: The restructuring plasmid pGenesil-Twist shRNA was constructed successfully. After 48 h of culture, 80% of the cells expressed high-intensity GFP fluorescence and stability. The expression of Twist decreased significantly after the transfection of the Twist shRNA plasmid (P<0.05). Proliferation of the transfected Twist shRNA cells showed no difference with that of the A2780-nontransfection or A2780-si-control groups (P>0.05) but the adhesion ability of A2780 decreased dramatically (P<0.05). Expression of the E-cadherin protein increased, whereas that of the N-cadherin protein decreased compared with that in the A2780-nontransfection or A2780-si-control groups (P<0.05). Conclusion: Twist is essential for epithelial-mesenchymal transition, invasion, and metastasis of ovarian cancer.

Lack of Association Between the CYP1A1 Ile462Val Polymorphism and Endometrial Cancer Risk: a Meta-analysis

Wang, Xi-Wen,Zhong, Tian-Yu,Xiong, Yun-Hui,Lin, Hai-Bo,Liu, Qing-Yi Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.8

Purpose: Any association between the CYP1A1 Ile462Val polymorphism and endometrial cancer risk remains inconclusive. For a more precise estimate, we performed the present meta-analysis. Methods: PUBMED, OVID and EMBASE were searched for the studies which met inclusion criteria. Data in all eligible studies were evaluated and extracted by two authors independently. The meta-analysis estimated pooled odds ratio (OR) with 95% confidence interval (CI) for endometrial cancer risk attributable to the CYP1A1 Ile462Val polymorphism. Results: A total of 7 studies were included in this meta-analysis. The results indicated no association between endometrial cancer risk and the CYP1A1 Ile462Val polymorphism (for Val vs Ile allele model [OR 1.09, 95% CI 0.73-1.62]; for Val.Val vs Ile.Ile genotype model [OR 1.54, 95% CI 0.56-4.23]; for (Ile.Val + Val.Val) vs Ile.Ile genotpye model [OR 1.08, 95% CI 0.71-1.63]; for Val.Val vs (Ile.Ile + Ile.Val) genotype model [OR 1.46, 95% CI 0.53-4.04]). Conclusions: This meta-analysis suggests that there is no association between endometrial cancer risk and the CYP1A1 Ile462Val polymorphism.

Toll-like Receptor 5 Agonism Protects Mice from Radiation Pneumonitis and Pulmonary Fibrosis

Wang, Zhi-Dong,Qiao, Yu-Lei,Tian, Xi-Feng,Zhang, Xue-Qing,Zhou, Shi-Xiang,Liu, Hai-Xiang,Chen, Ying Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.9

Radiation pneumonitis and pulmonary fibrosis are the main complications with radiotherapy for thoracic neoplasms, directly limiting the efficient dose in clinical application and currently there are few medicines that effectively function as radioprotectants. However, a TLR5 agonist, CBLB502, was confirmed to have protective efficacy against hematopoietic and gastrointestinal radiation syndromes in mice and primates. This study points to a new direction for protection against thoracic radiation-induced pulmonary syndromes and skin injury by CBLB502. We utilized the TUNEL assay, pathological analysis and immunohistochemistry to obtain evidence thatCBLB502 could alleviate the occurrence of radiation pneumonitis and pulmonary fibrosis as well as radiation-induced skin injury. It may thus play a promising role in facilitating clinical radiotherapy of thoracic neoplasms.

Meta-analysis of Associations of the Ezrin Gene with Human Osteosarcoma Response to Chemotherapy and Prognosis

Wang, Zhe,He, Mao-Lin,Zhao, Jin-Min,Qing, Hai-Hui,Wu, Yang Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.5

Various studies examining the relationship between Ezrin overexpression and response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. We accordingly conducted a meta-analysis of 7 studies (n = 318 patients) that evaluated the correlation between Ezrin and histologic response to chemotherapy and clinical prognosis (death). Data were synthesized in receiver operating characteristic curves and with fixed-effects and random-effects likelihood ratios and risk ratios. Quantitative synthesis showed that Ezrin is not a prognostic factor for the response to chemotherapy. The positive likelihood ratio was 0.538 (95% confidence interval [95% CI], 0.296- 0.979; random-effects calculation), and the negative likelihood ratio was 2.151 (95% CI, 0.905- 5.114; random-effects calculations). There was some between-study heterogeneity, but no study showed strong discriminating ability. Conversely, Ezrin positive status tended to be associated with a lower 2-year survival (risk ratio, 2.45; 95% CI, 1.26-4.76; random-effects calculation) with some between-study heterogeneity that disappeared when only studies that employed immunohistochemistry were considered (risk ratio, 2.97; 95% CI, 2.01- 4.40; fixed-effects calculation). To conclude, Ezrin is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas Ezrin positivity was associated with a lower 2-year survival rate regarding risk of death at 2 years. Expression change of Ezrin is an independent prognostic factor in patients with osteosarcoma.