PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma

Objective. Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. PLOD family was mainly involved in lysyl hydroxylation and rarely investigated in cancers, especially in osteosarcoma. The aim of this study was to investigate the expression pattern and oncogenic role of PLODs in osteosarcoma. Methods. GEO datasets (GSE16088, GSE33382, and GSE16091) and validation cohort were used to analyze the expression pattern of PLODs in osteosarcoma. Kaplan-Meier survival analysis was used to explore the prognostic role of PLODs in patients with osteosarcoma. RNA interference of KRT19 was performed using small interfering RNA (siRNA) in MG-63 and U-2OS cells. The proliferation was detected using CCK8, clone formation assay, and EdU staining. Migration and invasion were determined using the transwell assay. Western blots and luciferase assays for β-catenin-T-cell factor protein/β-catenin-lymphoid enhancer factor- (β-catenin-TCF/LEF-) driven transcriptional activity. Results. PLOD1 was upregulated in osteosarcoma tissues compared with control tissues both in public datasets and in in-house cohort. The expression of PLOD1 in osteosarcoma tissues was significantly associated with the status of distance metastasis and Enneking stage, while PLOD2 and PLOD3 expressed no difference between osteosarcoma and benign tissues and showed no correlation with tumor malignancy. Furthermore, Kaplan-Meier survival analysis revealed that patients with a higher level of PLOD1 had worse prognosis than those with a lower level of PLOD1. Downregulation of PLOD1 dramatically inhibited proliferation, migration, and invasion of MG-63 cells and U-2OS cells in vitro. Mechanistically, PLOD1 regulated β-catenin signaling pathway in osteosarcoma. Conclusion. Our results indicated that PLOD1 promoted proliferation, migration, and invasion of osteosarcoma cells. PLOD1 was a novel prognostic marker, as well as a therapeutic target in osteosarcoma.

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E2F2 inhibition induces autophagy to impair metastasis via the PI3K/Akt/mTOR pathway in gastric cancer

10.21203/rs.3.rs-97865/v1 ◽

2020 ◽

Author(s):

Hui Li ◽

Shufen Zhao ◽

Liwei Shen ◽

Peige Wang ◽

Shihai Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Cox Regression ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Kaplan Meier ◽

Patient Prognosis ◽

Public Datasets

Abstract Background: E2F2 is a member of the E2F family of transcription factors with important yet incompletely understood biological functions in cancer. In some cancer types, controversial tumor-promoting and tumor-suppressive roles of E2F2 have been reported. However, the biological role of E2F2 in gastric cancer (GC) remains to be determined. Methods: We analyzed E2F2 expression via multiple gene expression databases. The prognostic value of the E2F2 was determined by Kaplan-Meier Plotter and Cox regression. The correlations between E2F2 and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER). The functions and pathways of E2F2 and its 50 frequently changed genes closely associated with the family members were analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) software. We used immunohistochemistry (IHC), quantitative real-time PCR (qPCR) and western blot to verify the expression level of E2F2 in GC and further studied the effects of E2F2 on PI3K/Akt/mTOR activity; GC cell autophagy, migration, and invasion through wound healing assays, transwell assays, Western blotting, and transmission electron microscopy.Results: We observed that compared with normal gastric tissues/cells, E2F2 is highly expressed in gastric cancer tissues and cells in both the public datasets and in our experimental verification. High E2F2 expression was associated with poorer overall survival (OS). Moreover, E2F2 expression showed strong correlations with diverse immune marker sets in GC. Moreover, E2F2 overexpression promoted GC cell migration and invasion in vitro by inactivating PI3K/Akt/mTOR-mediated autophagy. Conversely, E2F2 inhibition suppressed GC cell migration and invasion in vitro by activating PI3K/Akt/mTOR-mediated autophagy.Conclusions: In conclusion, this study provides multi-level evidence for the importance of E2F2 in gastric carcinogenesis and its potential as a biomarker in GC. We demonstrated that E2F2 is overexpressed in GC and that high E2F2 expression is associated with aggressive tumor features and poorer patient prognosis. Further, our results suggest a potential novel immune regulatory role of E2F2 in tumor immunity. Functionally, we discovered a new role of E2F2 in regulating PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion. Our results could potentially reveal new targets and strategies for GC diagnosis and treatment.

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Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000484586 ◽

2017 ◽

Vol 44 (1) ◽

pp. 99-109 ◽

Cited By ~ 7

Author(s):

Fang Yang ◽

Lizhi Lv ◽

Kun Zhang ◽

Qiucheng Cai ◽

Jianyong Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Flow Cytometric Analysis ◽

Vital Role ◽

Migration And Invasion ◽

Flow Cytometric ◽

Kaplan Meier ◽

Proliferation Assays ◽

The Relationship

Background/Aims: Increasing evidence has indicated that Forkhead box protein C2 (FOXC2) plays an important role in carcinogenesis. However, the expression and the role of FOXC2 in hepatocellular carcinoma (HCC) have not been extensively studied. Methods: FOXC2 expression was analyzed by quantitative real-time polymerase chain reaction, Western blot analysis and immunohistochemistry in HCC tissue and cells. The relationship between FOXC2 expression and patient clinical significance and survival were assessed by Pearson’s correlation and Kaplan-Meier analysis, respectively. Cell proliferation assays, colony formation assays, flow cytometric analysis and Transwell assays were employed to measure the effects of FOXC2 on HCC cells in vitro. Results: The expression of FOXC2 was increased in HCC tissue, and high FOXC2 expression was associated with worse patient survival. Knockdown of FOXC2 inhibited HCC cell growth, migration, and invasion in vitro, as well as tumor growth. Furthermore, we found that activation of AKT-mediated MMP-2 and MMP-9 was involved in FOXC2 promoting an aggressive phenotype. Conclusions: Taken together, these findings demonstrate that FOXC2 is upregulated in HCC tissue and is associated with tumor size, vascular invasion and advanced TNM stage. Further investigation suggested that FOXC2 may play a vital role in promoting proliferation and invasion in HCC and serves as a novel therapeutic target in HCC.

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CircRNA UBAP2 Serves as a Sponge of miR-1294 to Increase Tumorigenesis in Hepatocellular Carcinoma through Regulating c-Myc Expression

10.21203/rs.3.rs-49281/v1 ◽

2020 ◽

Author(s):

Min-Cheng Yu ◽

Guang-Yu Ding ◽

Pei-Yao Fu ◽

Peng Ma ◽

Xiao-Dong Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Biomarker ◽

Migration And Invasion ◽

Circular Rnas ◽

Western Blots ◽

Paired Samples ◽

Polymerase Chain ◽

Regulatory Rnas

Abstract Background: Circular RNAs (circRNAs) are a class of regulatory RNAs with complex roles in healthy and diseased tissues. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) remains poorly understood, including the mechanisms by which the circRNA UBAP2 contributes to tumorigenesis. Methods: We analyzed the expression of circUBAP2 in 20 paired samples of HCC and healthy tissue as well as in seven HCC cell lines via quantitative real-time polymerase chain reaction (qRT-PCR). Functional experiments, such as CCK8 viability assays, colony formation assays, wound healing, transwell assays, and flow cytometry, were conducted to assess the effects of circUBAP2 in vitro. To further elucidate the mechanisms by which circUBAP2 acts, we conducted dual-luciferase assays, western blots, RNA pull-down assays, and rescue experiments. Results: circUBAP2 was highly upregulated in most HCC tissues and was associated with poor prognosis. HCC patients with high circUBAP2 expression had greater vascular invasion and worse differentiation. Functionally, circUBAP2 overexpression enhanced HCC cell proliferation, migration, and invasion and inhibited apoptosis. Furthermore, we found that circUBAP2 upregulated c-Myc expression by sponging miR-1294, thus contributing to hepatocarcinogenesis. Inhibiting circUBAP2 expression in HCC attenuated the oncogenic effects of c-Myc. Conclusions: These findings suggest that circUBAP2 promotes HCC growth and metastasis. circUBAP2 may have value as an independent prognostic biomarker or as a new target for the treatment of HCC.

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Overexpression of PELP1 in Lung Adenocarcinoma Promoted E2 Induced Proliferation, Migration and Invasion of the Tumor Cells and Predicted a Worse Outcome of the Patients

Pathology & Oncology Research ◽

10.3389/pore.2021.582443 ◽

2021 ◽

Vol 27 ◽

Author(s):

Dongmei Zhang ◽

Jiali Dai ◽

Yu Pan ◽

Xiuli Wang ◽

Juanjuan Qiao ◽

...

Keyword(s):

Cell Proliferation ◽

Lung Adenocarcinoma ◽

Clinicopathological Parameters ◽

Migration And Invasion ◽

Analysis Tool ◽

Cell Lung Carcinoma ◽

Kaplan Meier ◽

The Status ◽

Kaplan Meier Plotter

The expression of Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) has been reported to be dysregulated in non-small cell lung carcinoma, especially in lung adenocarcinoma (LUAD). Therefore, we aimed to investigate the functional and prognostic roles of PELP1 in LUAD in this study. We first immunolocalized PELP1 in 76 cases of LUAD and 17 non-pathological or tumorous lung (NTL) tissue specimens and correlated the findings with the clinicopathological parameters of the patients. We then performed in vitro analysis including MTT, flow cytometry, wound healing, and transwell assays in order to further explore the biological roles of PELP1 in 17-β-estradiol (E2) induced cell proliferation, migration, and invasion of LUAD cells. We subsequently evaluated the prognostic significance of PELP1 in LUAD patients using the online survival analysis tool Kaplan-Meier Plotter. The status of PELP1 immunoreactivity in LUAD was significantly higher than that in the NTL tissues and significantly positively correlated with less differentiated features of carcinoma cells, positive lymph node metastasis, higher clinical stage as well as the status of ERα, ERβ, and PCNA. In vitro study did reveal that E2 promoted cell proliferation and migration and elevated PELP1 protein level in PELP1-high A549 and H1975 cells but not in PELP1-low H-1299 cells. Knock down of PELP1 significantly attenuated E2 induced cell proliferation, colony formation, cell cycle progress as well as migration and invasion of A549 and H1975 cells. Kaplan-Meier Plotter revealed that LUAD cases harboring higher PELP1 expression had significantly shorter overall survival. In summary, PELP1 played a pivotal role in the estrogen-induced aggressive transformation of LUAD and could represent adverse clinical outcome of the LUAD patients.

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Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

Cell Death and Disease ◽

10.1038/s41419-021-03424-1 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Anqi Xu ◽

Xizhao Wang ◽

Jie Luo ◽

Mingfeng Zhou ◽

Renhui Yi ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Tumor Grade ◽

Prognostic Indicator ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Kaplan Meier ◽

Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

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Oncogenic UBE3C promotes breast cancer progression by activating Wnt/β-catenin signaling

Cancer Cell International ◽

10.1186/s12935-020-01733-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chen Hang ◽

Shanojie Zhao ◽

Tiejun Wang ◽

Yan Zhang

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Nuclear Accumulation ◽

Migration And Invasion ◽

Ubiquitin Protein Ligase ◽

Novel Target ◽

First Time ◽

Breast Tissues

Abstract Background Breast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized. Methods Immunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa. Results In this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells. Conclusion Collectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.

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Factors Affecting the Recurrence of Giant Cell Tumor of Bone After Surgery: A Clinicopathological Study of 80 Cases from a Single Center

Cellular Physiology and Biochemistry ◽

10.1159/000430164 ◽

2015 ◽

Vol 36 (5) ◽

pp. 1961-1970 ◽

Cited By ~ 13

Author(s):

Dong-dong Cheng ◽

Tu Hu ◽

Hui-zhen Zhang ◽

Jin Huang ◽

Qing-cheng Yang

Keyword(s):

Giant Cell Tumor ◽

Pathological Fracture ◽

Cell Tumor ◽

Migration And Invasion ◽

Ki 67 ◽

Factors Affecting ◽

Surgical Method ◽

Kaplan Meier ◽

Cd147 Expression

Background/Aims: This aim of the present study was to identify specific markers determining the recurrence of the giant cell tumor of bone (GCTB). Methods: This study involved the clinicopathological analysis of 80 cases. All of the clinical features, pathological fracture, Campanacci grade, histological features and surgical methods were reviewed. Immunohistochemistry was used to detect the expression of Ki-67, CD147, mutant p53 and p63 in GCTB. Comparisons between different groups were performed using the Chi-square test. The risk factors affecting recurrence were analyzed using a binary logistic model. Kaplan-Meier analysis was employed for the survival analysis between the groups. Cell proliferation assays, migration and invasion assays were used to detect the function of CD147 on GCTB in vitro. Results: The univariate analysis showed that Ki-67 and CD147 expression, pathological fracture, Campanacci grade and surgical method were associated with recurrence. The multivariate analysis revealed that CD147 expression, Campanacci grade and surgical method were the factors affecting GCTB recurrence. In addition, the Kaplan-Meier analysis revealed that these factors affected tumor-free survival time. In vitro study revealed that the CD147 knockdown by small interfering RNA (siRNA) technique dramatically reduced the proliferation, migration and invasion of GCTB. Conclusion: Our results suggest that CD147 may serve as an adequate marker for GCTB recurrence. Campanacci grade is a risk factor for GCTB recurrence, which is also affected by the surgical method used.

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HOXB7 acts as an oncogenic biomarker in head and neck squamous cell carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02093-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiang Wu ◽

Jin Li ◽

Tingyuan Yan ◽

Xueping Ke ◽

Xin Li ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Expression Pattern ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Clinicopathological Parameters ◽

Migration And Invasion ◽

Connectivity Map

Abstract Background The homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC. Methods HOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7. Results Bioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients’ overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC. Conclusions Our findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC.

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Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽

10.1161/str.52.suppl_1.p780 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Francisco J Gonzalez-Gonzalez ◽

Perike Srikanth ◽

Andrielle E Capote ◽

Alsina Katherina M ◽

Benjamin Levin ◽

...

Keyword(s):

Atrial Fibrillation ◽

Light Chain ◽

Myosin Light Chain ◽

Molecular Mechanisms ◽

Contractile Function ◽

Right Atrial ◽

Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

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Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

Circulation Research ◽

10.1161/res.129.suppl_1.p458 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Francisco J Gonzalez-Gonzalez ◽

Srikanth Perike ◽

Frederick Damen ◽

Andrielle Capote ◽

Katherina M Alsina ◽

...

Keyword(s):

Atrial Fibrillation ◽

Light Chain ◽

Myosin Light Chain ◽

Molecular Mechanisms ◽

Contractile Function ◽

Right Atrial ◽

Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

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