FSTL1 increases cisplatin sensitivity in epithelial ovarian cancer cells by inhibition of NF-κB pathway. Liu Ya-Kun,Jia Ya-Jing,Liu Shi-Hao,Ma Jing Cancer chemotherapy and pharmacology OBJECTIVE:To investigate the effects of FSTL1-mediated NF-κB signaling pathway on cisplatin (DDP) sensitivity of EOC cells. METHODS:FSTL1 expression was determined in epithelial ovarian cancer (EOC) tissues and corresponding adjacent tissues using immunohistochemistry. SKOV3 and SKOV3/DDP cells were transfected and grouped into Blank, Vector, and FSTL1 groups. The sensitivity and 50% inhibitory concentration (IC50) of cells treated with different concentrations of DDP were detected by MTT assay. SKOV3/DDP cells were treated with 20 μM DDP, followed by evaluation of cell proliferation, cell apoptosis and determination of NF-κB pathway-related proteins while SKOV3 cells without. RESULTS:FSTL1 expression in EOC tissues and cells was significantly down-regulated, especially decreased in DDP-resistant EOC cells SKOV3/DDP. In SKOV3 cells and SKOV3/DDP cells, the cell viability was reduced and the DDP sensitivity was improved with the decreased IC50 after over-expressing FSTL1. Compared with Blank group, FSTL1 group had declined number of SKOV3 cell colonies and increased cell apoptosis, with obvious up-regulations of FSTL1, Bax/Bcl-2 and cleaved caspase-3 expression and the down-regulations of p-IκBα, p-p65 and survivin expression. Combination of up-regulation of FSTL1 and DDP treatment can also effectively reduce cell colony forming, increase cell apoptosis, and inhibit NF-κB pathway activity of SKOV3/DDP cells. Moreover, this combination can also significantly suppress the growth of subcutaneous xenograft tumors in nude mice. CONCLUSION:FSTL1 may inhibit NF-κB signaling pathway to suppress the growth and promote the apoptosis of epithelial ovarian cancer cells, and thereby enhancing its DDP sensitivity. 10.1007/s00280-020-04215-9
    Cell type specific expression of Follistatin-like 1 (Fstl1) in mouse embryonic lung development. Liu Xue,Liu Yingying,Yang Zaofeng,Ning Wen Journal of molecular histology Follistatin like-1 (Fstl1) is a secreted glycoprotein and can be up-regulated by TGF-β1. To better study the function of Fstl1 in lung development, we examined Fstl1 expression in the developing lung, in a cell type specific manner, using a tamoxifen inducible Fstl1-reporter mouse strain. Our results show that Fstl1 is ubiquitously expressed at saccular stage in the developing lung. At E18.5, Fstl1 expression is robust in most type of mesenchymal cells, including airway smooth muscle cells surrounding airways, vascular smooth muscle cells, endothelial cells, and vascular pericytes from blood vessel, but not PDGFRα fibroblasts in the distal alveolar sacs. Meanwhile, relative weak and sporadic signals of Fstl1 expression are observed in epithelium, including a subgroup of club cells in proximal airways and a few type II alveolar epithelial cells in distal airways. Our data help to understand the critical role of Fstl1 in lung development and lung disease pathogenesis. 10.1007/s10735-018-9780-5
    FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation. Cheng Shaoqiang,Huang Yuanxi,Lou Chun,He Yanxia,Zhang Yue,Zhang Qingyuan Cancer biology & therapy FSTL1 is a protein coding gene associated with cell signaling pathway regulation and the progression of a variety of disorders. In this study, we hypothesized that FSTL1 increases oncogenesis in breast cancer by enhancing stemness and chemoresistance. RT-PCR and IHC revealed significantly higher FSTL1 mRNA and protein levels in TNBC than in non-TNBC specimens and in breast cancer cell lines. We then found that FSTL1 levels were significantly increased in chemoresistant cells. LIVE/DEAD, MTT cell viability and colony formation assays did in fact demonstrate that FSTL1 is required for CDDP and DOX chemoresistance in breast cancer cell lines. FSTL1 overexpression caused significant elevation of stem cell biomarkers, as well as breast cancer cell proliferation. To determine whether the Wnt/β-catenin signaling pathway is involved in the observed effects of FSTL1, we assessed levels of pathway target. TOP/FOP flash, colony formation, and tumor sphere formation assays indicated that FSTL1 activates Wnt/β-catenin signaling through integrin β3. We then sought to identify a microRNA (miRNA) that regulates FSTL1 activity. Luciferase assays demonstrated that miR-137 reduces FSTL1 mRNA and protein levels. Ultimately, our findings indicate that there is an miR-137/FSTL1/integrin β3/Wnt/β-catenin signaling axis in breast cancer cells that regulates stemness and chemoresistance. 10.1080/15384047.2018.1529101
    FSTL1 promotes nitric oxide-induced chondrocyte apoptosis via activating the SAPK/JNK/caspase3 signaling pathway. Xu Chao,Jiang Tao,Ni Su,Chen Chaoqun,Li Chenkai,Zhuang Chao,Zhao Gongyin,Jiang Shijie,Wang Liangliang,Zhu Ruixia,van Wijnen Andre J,Wang Yuji Gene OBJECTIVE:Previous studies have shown that follistatin-like protein 1 (FSTL1) is elevated in the synovial fluid of osteoarthritis and is associated with disease activity. The experiment was performed to stuy the effect and mechanism of FSTL1 on chondrocyte apoptosis in osteoarthritis. DESIGN:After the isolation of human normal and osteoarthritis (OA) chondrocytes, the expression of FSTL1 was detected by Q-PCR and western blot analyses. Chondrocytes were pre-transfected with FSTL1 overexpression plasmids then treated with SNP, and chondrocyte viability and apoptosis levels were detected by MTS and flow cytometry, respectively. Cartilage matrix gene expression was measured by Q-PCR and signal pathway-related proteins were assessed by western blot. RESULTS:The expression of FSTL1 in OA chondrocytes was markedly up-regulated compared with normal human chondrocytes (P < 0.05). The apoptosis rate of chondrocytes in the FSTL1 overexpression groups was highly elevated in the comparison with the negative control groups (P < 0.05). Additionally, FSTL1 potentiated protein abundances of MMP1, MMP3, MMP-9, and Bax as well as reduced Coll2a1 and Aggrecan and Bcl-2 expression. Furthermore, western blot results showed that the SAPK/JNK/Caspase3 signal pathway was significantly activated and the Ac-DEVD-FMK impaired FSTL1 induced chondrocyte apoptosis. CONCLUSION:FSTL1 promoted SNP-induced chondrocytes apoptosis by activating the SAPK/JNK/Caspase3 signal pathway. 10.1016/j.gene.2020.144339
    Persistent Myocardial Production of Follistatin-like 1 Is Associated With Left Ventricular Adverse Remodeling in Patients With Myocardial Infarction: Myocardial production of FSTL1 in AMI patients. Uematsu Manabu,Nakamura Kazuto,Nakamura Takamitsu,Watanabe Yosuke,Yoshizaki Toru,Deyama Juntaro,Kobayashi Tsuyoshi,Fujioka Daisuke,Saito Yukio,Kawabata Kenichi,Obata Jun-Ei,Kugiyama Kiyotaka Journal of cardiac failure BACKGROUND:Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction. METHODS AND RESULTS:FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and -0.43, respectively, all P < .001). CONCLUSIONS:The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction. 10.1016/j.cardfail.2020.05.015
    Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases. Li Xiaohe,Fang Yinshan,Jiang Dingyuan,Dong Yingying,Liu Yingying,Zhang Si,Guo Jiasen,Qi Chao,Zhao Chenjing,Jiang Fangxin,Jin Yueyue,Geng Jing,Yang Cheng,Zhang Hongkai,Wei Bin,Liang Jiurong,Wang Chen,Dai Huaping,Zhou Honggang,Jiang Dianhua,Ning Wen Molecular therapy : the journal of the American Society of Gene Therapy Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-β1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-β1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases. 10.1016/j.ymthe.2020.09.031
    Follistatin-like 1 (FSTL1) is a prognostic biomarker and correlated with immune cell infiltration in gastric cancer. Li Li,Huang Shanshan,Yao Yangyang,Chen Jun,Li Junhe,Xiang Xiaojun,Deng Jun,Xiong Jianping World journal of surgical oncology BACKGROUND:Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated. METHODS:The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real-time quantitative PCR (RT-qPCR) were used to analyze protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates were analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA), and LinkedOmics database. RESULTS:The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC. CONCLUSIONS:The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks, and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC. 10.1186/s12957-020-02070-9
    Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease. Maksimowski Nicholas A,Song Xuewen,Bae Eun Hui,Reich Heather,John Rohan,Pei York,Scholey James W,Nephrotic Syndrome Study Network Neptune International journal of molecular sciences Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 () was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the receptors, and , increased in both mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope (Advanced Cell Diagnostics, Newark CA, USA) localized to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline mRNA levels. is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD. 10.3390/ijms22179513
    Follistatin-like 1: A dual regulator that promotes cardiomyocyte proliferation and fibrosis. Hu Siyuan,Liu Hua,Hu Zhixi,Li Lin,Yang Yi Journal of cellular physiology Follistatin-like 1 (FSTL1) is a key factor in maintaining cardiac growth and development. It can be activated by exercise training and has a dual role in promoting cardiomyocyte proliferation and fibrosis, but its underlying mechanism is not fully understood. To elucidate the dual mechanism and target of FSTL1 regulating of cardiomyocyte proliferation and myocardial fibrosis, and the mechanism by which exercise-regulated FSTL1 improves cardiovascular disease, we explored the signal transduction pathway of FSTL1 promoting cardiomyocyte proliferation and fibrosis, and compared the effects of different modes of exercise on the dual role of FSTL1. We believe that the dual role of promoting cardiomyocyte proliferation and fibrosis may be related to the ratio of cardiomyocyte and myocardial interstitial cell proliferation, different stages of the disease, different degrees of fibrosis, immune repair process, and transforming growth factor-β activation. Compared with long-term excessive endurance exercise, moderate resistance exercise can activate cardiomyocyte proliferation pathway through FSTL1, which is one of the effective ways to prevent cardiovascular disease. 10.1002/jcp.29588
    Structural and functional study of FK domain of Fstl1. Li Xinxin,Li Lian,Chang Yue,Ning Wen,Liu Xinqi Protein science : a publication of the Protein Society Fstl1 is a TGF-β superfamily binding protein which involved in many pathological processes. The function of Fstl1 has been widely elucidated, but its structural characterization has not been explored. Here we solved the high-resolution crystal structure of FK domain of murine Fstl1, analyzed its unique characteristics, and investigated its contribution to the function of full-length Fstl1. We found that Fstl1-FK forms a stable dimer in both solution and crystal, which suggest that this protein may function as a dimer during its interaction with TGF-β, a molecule known to form dimer during activation process. We also found this FK domain is indispensable for the proper function of Fstl1 during the transduction of TGF-β signaling. These observations provide important insights into the understanding of Fstl1 and may facilitate the exploration of this molecule in clinical study. 10.1002/pro.3696
    FSTL1 secreted by activated fibroblasts promotes hepatocellular carcinoma metastasis and stemness. Loh Jia Jian,Li Tsz Wai,Zhou Lei,Wong Tin Lok,Liu Xue,Ma Victor Ws,Lo Chung Mau,Man Kwan,Lee Terence K,Ning Wen,Tong Man,Ma Stephanie Cancer research The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it develops in the setting of fibrosis and cirrhosis. This pathological state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a pro-inflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL4-induced hepatic fibrosis mouse model. Clinically, high FSTL1 in FAP+ fibroblasts were significantly correlated with more advanced tumors in HCC patients. Although FSTL1 was expressed in primary fibroblasts derived from HCC patients, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a pre-clinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC. 10.1158/0008-5472.CAN-20-4226
    FSTL1 promotes growth and metastasis in gastric cancer by activating AKT related pathway and predicts poor survival. Wu Mengjie,Ding Yongfeng,Wu Nan,Jiang Junjie,Huang Yingying,Zhang Fanyu,Wang Haiyong,Zhou Quan,Yang Yan,Zhuo Wei,Teng Lisong American journal of cancer research Accumulating evidence on the role of Follistatin-like protein 1 (FSTL1) in tumorigenesis and cancer progression is conflicting. Nevertheless, the underlying mechanisms by which FSTL1 contributes to gastric cancer (GC) remain unknown. This study shows that FSTL1 was frequently upregulated in primary GC tissues and significantly correlated with infiltrating depth, lymph node metastasis, unfavorable tumor stage and poor prognosis of GC. Down or up-regulation of FSTL1 inhibited or increased, respectively, the proliferation by reducing apoptosis, clonogenicity, migration and invasion of GC cells . Moreover, the higher expression of FSTL1 promoted subcutaneous xenograft tumor growth and lung/liver tumor metastasis . Furthermore, we demonstrate that FSTL1 is involved in regulation of the AKT signaling through analyzing databases and experimental results. Mechanistic studies showed that FSTL1 promoted proliferation, migration and invasion in GC, at least partially, by activating AKT via regulating TLR4/CD14. In all, this study highlights the role of the FSTL1-TLR4/CD14-AKT axis, which provided novel insights into the mechanism of growth and metastasis in GC for the first time.