Abstract 1981: TGF-β induced PLEK2 promotes metastasis and chemoresistance in ESCC by up-regulation of LCN2

Abstract

Abstract Background: Esophageal squamous cell carcinoma (ESCC) patients suffer from poor prognosis in general. Novel molecular markers to predict prognosis and serve as potential therapy target are much needed. Our previous research has established a comprehensive database of ESCC (GSE53625). Combined with data from TCGA, we found Pleckstrin 2 (PLEK2) predicts poor prognosis in ESCC. Meanwhile, its role in ESCC progression remains unknown. Methods: The TCGA database and GSE53625 are used to establish the expression profiles of PLEK2 and overall survival rates. Loss-of-function assays were performed to examine the effect of PLEK2 on proliferation, migration and invasion of ESCC cells in vitro and in vivo. ChIP assay was used to detect the relationship between TGF-β and PLEK2. Western blot and quantitative real time PCR (qRT-PCR) were carried out to reveal the interrelation between PLEK2 and LCN2. Results: PLEK2 had a higher expression in ESCCs and predicted poor overall survival (OS). PLEK2 attenuation by shRNA was sufficient to decrease ESCC cells proliferation, clonogenicity, migration and invasion in vitro and tumorigenicity and distant metastasis in vivo. Conversely, elevating PLEK2 levels performed opposite effects. Downregulation of PLEK2 led to higher proportions of apoptotic ESCC cells when induced by Cisplatin. The high expression of PLEK2 in ESCC patients also linked to shorter OS of patients who received adjuvant chemotherapy. TGF-β could increase the expression of PLEK2 by stimulation of Smad2/3 which can bind directly with the promoter sequences of PLEK2. Analyses of transcriptome profiling suggested LCN2 as the downstream of PLEK2. Overexpression LCN2 in PLEK2 stable knockdown ESCC cells can reverse the decreased migration and invasion, but not the proliferation of ESCC cells. TGF-β increased the expression of LCN2, but the effect disappeared when PLEK2 was knockdown. We also find that AKT pathway is involved in the whole regulatory processes. Conclusion: Our results revealed the significance of PLEK2 in driving oncogenesis and metastasis in ESCC by regulating LCN2 which activates AKT pathway. We also indicated that PLEK2 was associated with chemo-resistance. Our findings indicates the potential use of PLEK2 as a prognostic biomarker and a candidate therapeutic target in ESCC. Keywords: PLEK2; ESCC; TGF-β; chemo-resistance Citation Format: Feng Wang, Chaoqi Zhang, Chengming Liu, Hong Cheng, Nan Sun, Jie He. TGF-β induced PLEK2 promotes metastasis and chemoresistance in ESCC by up-regulation of LCN2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1981.