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Table S2 from A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers

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posted on 2023-03-31, 20:43 authored by Haiyan Zhu, Xiang Gu, Lu Xia, You Zhou, Hakim Bouamar, Junhua Yang, Xiaofei Ding, Christian Zwieb, Jianan Zhang, Andrew P. Hinck, Lu-Zhe Sun, Xueqiong Zhu

Supplementary Table2. Gene Ontology Biological Processes that the differentially expressed probesets were enriched in

Funding

NIH

National Natural Science Foundation of China

Medical and Technology Project of Zhejiang Province

Cancer Therapy and Research Center

Second Affiliated Hospital of Wenzhou Medical University

Xiangya School of Medicine, Central South University, Hunan, China

Cancer Prevention and Research Institute of Texas (CPRIT)

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ARTICLE ABSTRACT

Purpose: We investigated the mechanisms of how TGFβ pathway is activated by chemotherapeutics and whether a novel TGFβ trap called RER can block chemotherapeutics-induced TGFβ pathway activation and enhance their antitumor activity in gynecologic cancer.Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGFβ signaling and function, and the effects of RER on chemotherapy-induced TGFβ signaling were determined in gynecologic cancer cells.Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGFβ signaling activation. Chemotherapy was found to activate TGFβ signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGFβ1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial–mesenchymal transition (EMT) and cancer stem cells (CSC). These TGFβ-like effects were due to the stimulation of TGFβ1 expression and secretion, and could all be abrogated by TGFβ inhibitors including a novel TGFβ trap protein called RER both in vitro and in vivo. Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer.Conclusions: Chemotherapeutics can stimulate TGFβ1 production and consequently enhance TGFβ signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGFβ inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. Clin Cancer Res; 24(12); 2780–93. ©2018 AACR.

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    Clinical Cancer Research

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    Biological Agents & TherapiesAntireceptorsCell SignalingAutocrine-paracrine signalingDrug MechanismsDrug TargetsOncoprotein & tumor suppressor drug targetsEndocrinologyGrowth factors and receptorsGynecological CancersCervical cancerOvarian cancerProgression, Invasion & MetastasisMigration and invasion

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