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Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib

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Cancer Communications 2023年第4期43卷 455-479页

作者： JungWoo Eun Jung Hwan Yoon Hye Ri Ahn Seokhwi Kim Young Bae Kim Su Bin Lim Won Park TaeWook Kang Geum Ok Baek Moon Gyeong Yoon Ju A Son Ji HyangWeon Soon Sun Kim Hyo Jung Cho Jae Youn Cheong Department of Gastroenterology Ajou University School of MedicineSuwonSouth Korea Department of Pathology College of MedicineThe Catholic University of KoreaSeoulSouth Korea Department of Biomedical Sciences AjouUniversity Graduate School of MedicineSuwonSouth Korea Department of Pathology Ajou University School of MedicineSuwonSouth Korea Department of Biochemistry&Molecular Biology Ajou University School of MedicineSuwonSouth Korea The Moagen IncDaejeonSouth Korea

Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of *** study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to *** then performed in vitro and in vivo experiments to validate selected targets and related *** associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression ***:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI ***1 inhibitors reversed CAF-induced TKI resistance in vitro and in ***-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI ***:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT *** inhibition represents a promising therapeutic strategy against TKI resistance ***,plasma SPP1 level before TKI treatment represents a potential biomar

关键词： drug resistance epithelial-to-mesenchymal transition hepatocellular carcinoma secreted phosphoprotein 1

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A high level of secreted phosphoprotein 1 is associated with macrophage infiltration and poor prognosis in hepatocellular carcinoma

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iLIVER 2023年第1期2卷 26-35页

作者： Jianping Song Jingxian Sun Shuhong Jing Tingxiao Zhang Jianlei Wang Yanfeng Liu Department of Hepatobiliary Surgery Second Hospital of Shandong UniversityJinan 250012China Department of Surgery Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan 250012China Department of Organ Transplantation Qilu HospitalCheeloo College of MedicineShandong UniversityJinan 250012China Department of Hepatobiliary Surgery Qilu Hospital of Shandong UniversityJinan 250012China

Background and aims:secreted phosphoprotein 1(SPP1)functions in several physiological *** role of SPP1 expression in the prognosis and tumor immunity of hepatocellular carcinoma(HCC)is *** aim of this study was to investigate the expression pattern of SPP1 in HCC and its correlation with prognosis and tumor ***:Clinical and gene expression data of The Cancer Genome Atlas-liver hepatocellular carcinoma(LIHC)cohort and 11 other HCC datasets were *** Kaplan–Meier method and Cox regression analysis were used to analyze the prognostic value of *** DESeq2 package in R was used to analyze SPP1-related *** Ontology analysis and gene set enrichment analysis were used to determine the biological function of SPP1 in *** single sample Gene Set Enrichment Analysis(ssGSEA)method was used to analyze the immune infiltrates of *** human methylation 450 data and level 3 HTSeq-FPKM data from The Cancer Genome Atlas-LIHC were used to analyze the effects of DNA methylation level on SPP1 ***:SPP1 was overexpressed in HCC and correlated with T stage,histological grade,adjacent hepatic tissue inflammation,and vascular invasion in *** analysis of survival rates indicated that high SPP1 levels were associated with poor overall survival in *** analysis showed that SPP1 is related to tumor immunity,especially macrophage *** demethylation of the promoter region is one of the mechanisms underlying the increase of SPP1 in ***:Our results indicate that SPP1 is an independent prognostic factor for HCC and is correlated with the clinical features and macrophage infiltration in HCC.

关键词： Hepatocellular carcinoma secreted phosphoprotein 1 Prognosis Promoter demethylation Tumor immunity

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Select nutrients and their effects on conceptus development in mammals

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Animal Nutrition 2015年第3期1卷 85-95页

作者： Fuller W.Bazer Xiaoqiu Wang Greg A.Johnson Guoyao Wu Departments of Animal Science Texas A&M University Veterinary Integrative Biosciences Texas A&M University

The dialogue between the mammalian conceptus(embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients,collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of adult onset of metabolic diseases. Histotroph includes numerous amino acids, but arginine plays a particularly important role as a source of nitric oxide and polyamines required for fetal-placental development in rodents, swine and humans through mechanisms that remain to be fully elucidated. Mechanisms whereby arginine regulates expression of genes via the mechanistic target of rapamycin cell signaling pathways critical to conceptus development, implantation and placentation are discussed in detail in this review.

关键词： Amino acids secreted phosphoprotein 1 Pregnancy Interferon tau Conceptus development Trophectoderm

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