• Activin A as a Novel Chemokine Induces Migration of L929 Fibroblasts by ERK Signaling in Microfluidic Devices

      Jiang, Lingling; Qi, Yan; Kong, Xianghan; Wang, Runnan; Qi, Jianfei; Lin, Francis; Cui, Xueling; Liu, Zhonghui (Frontiers Media S.A., 2021-05-21)
      Activin A, a member of the transforming growth factor-beta (TGF-β) superfamily, contributes to tissue healing and fibrosis. As the innate tissue cells, fibroblasts also play an important role in wound healing and fibrosis. Herein, this study was aimed to investigate how activin A exhibited regulatory effects on adhesion and migration of fibroblasts. We found that activin A induced the migration of fibroblast cell line L929 cells in transwell chamber and microfluidic device. Activin A also promoted L929 cells adhesion, but did not affect L929 cells viability or proliferation. In addition, activin A induced α-SMA expression and TGF-β1 release, which were factors closely related to tissue fibrosis, but had no effect on IL-6 production, a pro-inflammatory cytokine. Furthermore, activin A elevated calcium levels in L929 cells and increased p-ERK protein levels. Activin A-induced migration of L929 cells was attenuated by ERK inhibitor FR180204. To conclude, these data indicated that activin A as a novel chemokine induced the chemotactic migration of L929 cells via ERK signaling and possessed the pro-fibrosis role. These findings provide a new insight into understanding of activin A in tissue fibrosis.
    • Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics

      Matias-Barrios, Victor M; Radaeva, Mariia; Song, Yi; Alperstein, Zaccary; Lee, Ahn R; Schmitt, Veronika; Lee, Joseph; Ban, Fuqiang; Xie, Ning; Qi, Jianfei; et al. (Frontiers Media S.A., 2021-02-01)
    • Identification of Prognostic Signature and Gliclazide as Candidate Drugs in Lung Adenocarcinoma

      Cheng, Yang; Hou, Kezuo; Wang, Yizhe; Chen, Yang; Zheng, Xueying; Qi, Jianfei; Yang, Bowen; Tang, Shiying; Han, Xu; Shi, Dongyao; et al. (Frontiers Media S.A., 2021-06-24)
      Background: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, with high incidence and mortality. To improve the curative effect and prolong the survival of patients, it is necessary to find new biomarkers to accurately predict the prognosis of patients and explore new strategy to treat high-risk LUAD. Methods: A comprehensive genome-wide profiling analysis was conducted using a retrospective pool of LUAD patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE18842, GSE19188, GSE40791 and GSE50081 and The Cancer Genome Atlas (TCGA). Differential gene analysis and Cox proportional hazard model were used to identify differentially expressed genes with survival significance as candidate prognostic genes. The Kaplan-Meier with log-rank test was used to assess survival difference. A risk score model was developed and validated using TCGA-LUAD and GSE50081. Additionally, The Connectivity Map (CMAP) was used to predict drugs for the treatment of LUAD. The anti-cancer effect and mechanism of its candidate drugs were studied in LUAD cell lines. Results: We identified a 5-gene signature (KIF20A, KLF4, KRT6A, LIFR and RGS13). Risk Score (RS) based on 5-gene signature was significantly associated with overall survival (OS). Nomogram combining RS with clinical pathology parameters could potently predict the prognosis of patients with LUAD. Moreover, gliclazide was identified as a candidate drug for the treatment of high-RS LUAD. Finally, gliclazide was shown to induce cell cycle arrest and apoptosis in LUAD cells possibly by targeting CCNB1, CCNB2, CDK1 and AURKA.
    • N 6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1

      Wang, Duo; Qu, Xiujuan; Lu, Wenqing; Wang, Yizhe; Jin, Yue; Hou, Kezuo; Yang, Bowen; Li, Ce; Qi, Jianfei; Xiao, Jiawen; et al. (Frontiers Media S.A., 2021-07-01)
      Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.
    • Succinylation Regulators Promote Clear Cell Renal Cell Carcinoma by Immune Regulation and RNA N6-Methyladenosine Methylation

      Lu, Wenqing; Che, Xiaofang; Qu, Xiujuan; Zheng, Chunlei; Yang, Xianghong; Bao, Bowen; Li, Zhi; Wang, Duo; Jin, Yue; Wang, Yizhe; et al. (Frontiers Media S.A., 2021-02-18)
      Succinylation is a newly discovered and multienzyme-regulated post-translational modification (PTM) that is associated with the initiation and progression of cancer. Currently, no systematic analyses on the role of succinylation regulators in tumors have been reported. In this study, we performed a comprehensive pan-cancer analysis on four well-known succinylation regulators (CPT1A, KAT2A, SIRT5, and SIRT7). We found that these regulators played specific and critical roles in the prognosis of clear cell renal cell carcinoma (ccRCC). We constructed a risk score (RS) based on two independent prognostic prediction factors, CPT1A and KAT2A, and subsequently developed a nomogram model containing the RS, which showed good accuracy in the prediction of overall survival (OS) in ccRCC patients. Furthermore, we used the similar expression pattern of four succinylation regulators according to consensus clustering analysis to divide the patients into three clusters that exhibited prominently different OS as well as clinicopathological characteristics. Differently expressed genes (DEGs) and pathway enrichment analyses of three clusters indicated that succinylation regulators might promote malignant progression of ccRCC by regulating the infiltration of immune cells and RNA N6-methyladenosine (m6A) methylation. Importantly, our data suggest that CPT1A and SIRT5 might up-regulate and down-regulate the expression of LRPPRC and EIF3B, respectively. Our study systematically analyzed the prognostic predictive values of four succinylation regulators and revealed their potential mechanisms in ccRCC aggressiveness. These data provide new insight into the understanding of succinylation modification and present clinical evidence for its role in ccRCC treatments.