
CLC number:
On-line Access: 2024-08-27
Received: 2023-10-17
Revision Accepted: 2024-05-08
Crosschecked: 2023-01-16
Cited: 0
Clicked: 3414
Citations: Bibtex RefMan EndNote GB/T7714
Jiahang MO, https://orcid.org/0000-0002-2418-1745
Jiahang MO, Shunyi RUAN, Baicai YANG, Yunfeng JIN, Keyi LIU, Xukai LUO, Hua JIANG. A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200272 @article{title="A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer", %0 Journal Article TY - JOUR
基于内质网应激相关基因构建新型风险模型用于卵巢癌预后及免疫浸润状态的预测1复旦大学附属妇产科医院,中国上海市,200011 2复旦大学附属妇产科医院上海市女性生殖内分泌相关疾病重点实验室,中国上海市,200011 3上海交通大学医学院附属第六人民医院肿瘤科,上海交通大学医学院,中国上海市,200233 4嘉兴学院附属妇幼保健院妇产科,中国嘉兴市,314050 5浙江大学医学院附属妇科医院病理科,中国杭州市,310006 目的:开发一种基于内质网应激相关基因的预后模型,可有效预测卵巢癌(OvCa)患者的总生存期和免疫浸润状态。 方法:首先从TCGA和GEO数据库下载了552例含有RNA测序及临床信息的OvCa病例数据;并从GeneCards中提取了785个被定义为内质网应激相关的基因。然后结合单因素Cox回归分析和LASSO回归分析建立基于内质网应激基因的预后模型。在TCGA队列训练后,我们又纳入两个外部数据集进行Kaplan-Meier生存分析和时间依赖性受试者工作特征曲线(ROC)分析验证了其预后预测的性能。此外,我们还进行了GO、KEGG和GSEA功能富集分析;应用CIBERSORT算法描绘了风险分组中免疫浸润状态差异。 创新点:OvCa是一种致死率极高的妇科恶性肿瘤,具有高度的侵袭性及肿瘤异质性。大量临床研究显示OvCa对免疫治疗的应答率极低,提示瘤内免疫浸润状态不佳。因此,需要开发更为可靠的基因标志物用于预测患者的预后和免疫浸润状态。研究显示,内质网应激相关通路与卵巢癌预后密切相关,但尚缺乏基于该通路相关基因的模型用以预测患者的临床预后。本研究基于内质网应激相关基因构建了一种新型风险模型,用于患者的预后风险分层和总体生存率预测。同时,基于对肿瘤免疫浸润状态评估,该风险模型提示内质网应激的选择性激活或可改善免疫治疗在OvCa中的疗效。 结论:本研究构建了由7个内质网应激相关基因构成的预后模型,可在训练集和验证集中有效区分高风险OvCa患者,并被证明为总生存期的独立预后因子。利用诺谟图进行基于该风险特征的生存率预测。后续分析显示高低风险人群存在内质网应激通路激活的分支差异。功能富集和免疫浸润分析表明该风险特征与肿瘤免疫应答状态密切相关。综上,基于内质网应激相关基因的预后模型是一种很有前景的工具,可进行风险分层、生存预测和免疫浸润状态的评估。 关键词组: Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article
Reference[1]AndrewsAM, TennantMD, ThaxtonJE, 2021. Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity. Cancer Immunol Immunother, 70(5):1165-1175. ![]() [2]BarezSR, AtarAM, AghaeiM, 2020. Mechanism of inositol-requiring enzyme 1-alpha inhibition in endoplasmic reticulum stress and apoptosis in ovarian cancer cells. J Cell Commun. Signal, 14(4):403-415. ![]() [3]BartoszewskiR, BrewerJW, RabA, et al., 2011. The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J Biol Chem, 286(48):41862-41870. ![]() [4]BerettaGL, CornoC, ZaffaroniN, et al., 2019. Role of FoxO proteins in cellular response to antitumor agents. Cancers (Basel), 11(1):90. ![]() [5]CaoLX, YuanXS, BaoFC, et al., 2019. Downregulation of HSPA2 inhibits proliferation via ERK1/2 pathway and endoplasmic reticular stress in lung adenocarcinoma. Ann Transl Med, 7(20):540. ![]() [6]ChemalyER, TronconeL, LebecheD., 2018. SERCA control of cell death and survival. Cell Calcium, 69:46-61. ![]() [7]ChenX, Cubillos-RuizJR, 2021. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer, 21(2):71-88. ![]() [8]ChengMY, YuHM, KongQH, et al., 2022. The mitochondrial PHB2/OMA1/DELE1 pathway cooperates with endoplasmic reticulum stress to facilitate the response to chemotherapeutics in ovarian cancer. Int J Mol Sci, 23(3):1320. ![]() [9]ChowK, BedőJ, RyanA, et al., 2021. Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival. Eur J Cancer, 148:440-450. ![]() [10]Cubillos-RuizJR, SilbermanPC, RutkowskiMR, et al., 2015. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell, 161(7):1527-1538. ![]() [11]Cubillos-RuizJR, BettigoleSE, GlimcherLH, 2016. Molecular pathways: immunosuppressive roles of IRE1α-XBP1 signaling in dendritic cells of the tumor microenvironment. Clin Cancer Res, 22(9):2121-2126. ![]() [12]FeiHJ, ChenSC, XuCM, 2021. Construction autophagy-related prognostic risk signature to facilitate survival prediction, individual treatment and biomarker excavation of epithelial ovarian cancer patients. J Ovarian Res, 14:41. ![]() [13]GalluzziL, BuquéA, KeppO, et al., 2017. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol, 17(2):97-111. ![]() [14]GaoJC, YangXJ, YinP, et al., 2012. The involvement of FoxO in cell survival and chemosensitivity mediated by Mirk/Dyrk1B in ovarian cancer. Int J Oncol, 40(4):1203-1209. ![]() [15]GarsedDW, AlsopK, FeredayS, et al., 2018. Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer. Clin Cancer Res, 24(3):569-580. ![]() [16]González-MartínA, PothuriB, VergoteI, et al., 2019. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med, 381(25):2391-2402. ![]() [17]GotoT, TakanoM, HirataJ, et al., 2008. The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers. Br J Cancer, 98(6):1068-1075. ![]() [18]HanLY, FletcherMS, UrbauerDL, et al., 2008. HLA class I antigen processing machinery component expression and intratumoral T-cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin Cancer Res, 14(11):3372-3379. ![]() [19]HarterP, SehouliJ, VergoteI, et al., 2021. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med, 385(23):2123-2131. ![]() [20]HuangTF, XuTQ, WangYF, et al., 2021. Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy, 17(11):3592-3606. ![]() [21]KasikovaL, HenslerM, TruxovaI, et al., 2019. Calreticulin exposure correlates with robust adaptive antitumor immunity and favorable prognosis in ovarian carcinoma patients. J Immunother Cancer, 7(1):312. ![]() [22]KimT, KoSG, 2021. JI017, a complex herbal medication, induces apoptosis via the Nox4-PERK-CHOP axis in ovarian cancer cells. Int J Mol Sci, 22(22):12264. ![]() [23]KuhlmannJD, SchwarzenbachH, OtterbachF, et al., 2011. Loss of heterozygosity proximal to the M6P/IGF2R locus is predictive for the presence of disseminated tumor cells in the bone marrow of ovarian cancer patients before and after chemotherapy. Genes Chromosomes Cancer, 50(8):598-605. ![]() [24]LeeJY, HamJ, LimW, et al., 2020. Apomorphine facilitates loss of respiratory chain activity in human epithelial ovarian cancer and inhibits angiogenesis in vivo. Free Radic Biol Med, 154:95-104. ![]() [25]LeiY, HendersonBR, EmmanuelC, et al., 2015. Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis. Oncogene, 34(4):485-495. ![]() [26]LeksaV, IlkováA, VičíkováK, et al., 2017. Unravelling novel functions of the endosomal transporter mannose 6-phosphate/insulin-like growth factor receptor (CD222) in health and disease: an emerging regulator of the immune system. Immunol Lett, 190:194-200. ![]() [27]LheureuxS, BraunsteinM, OzaAM, 2019. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin, 69(4):280-304. ![]() [28]LinJH, LiuH, FukumotoT, et al., 2021. Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer. Nat Commun, 12:5321. ![]() [29]LiuLY, YiJJ, YuanJH, et al., 2020. FOXO1 overexpression is correlated with poor prognosis in epithelial ovarian cancer. Cancer Biomark, 28(1):1-8. ![]() [30]LiuN, BaiLP, LuZP, et al., 2022. TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease. J Neuroinflamm, 19:26. ![]() [31]MillsteinJ, BuddenT, GoodeEL, et al., 2020. Prognostic gene expression signature for high-grade serous ovarian cancer. Ann Oncol, 31(9):1240-1250. ![]() [32]NicolayBN, DanielianPS, KottakisF, et al., 2015. Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation. Genes Dev, 29(17):1875-1889. ![]() [33]Ovarian Tumor Tissue Analysis (OTTA) Consortium, 2017. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol, 3(12):e173290. ![]() [34]PatchAM, ChristieEL, EtemadmoghadamD, et al., 2015. Whole-genome characterization of chemoresistant ovarian cancer. Nature, 521(7553):489-494. ![]() [35]PovedaA, FloquetA, LedermannJA, et al., 2021. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol, 22(5):620-631. ![]() [36]Pujade-LauraineE, HilpertF, WeberB, et al., 2014. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol, 32(13):1302-1308. ![]() [37]SabapathyK, NamSY, 2008. Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function. Cell Death Differ, 15(9):1364-1374. ![]() [38]ŚcieglińskaD, PiglowskiW, MazurekA, et al., 2008. The HspA2 protein localizes in nucleoli and centrosomes of heat shocked cancer cells. J Cell Biochem, 104(6):2193-2206. ![]() [39]SeoJA, KimB, DhanasekaranDN, et al., 2016. Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells. Cancer Lett, 371(1):30-37. ![]() [40]ShiMX, WhortonAE, SekulovskiN, et al., 2020. Inactivation of TRP53, PTEN, RB1, and/or CDH1 in the ovarian surface epithelium induces ovarian cancer transformation and metastasis. Biol Reprod, 102(5):1055-1064. ![]() [41]SojkaDR, Gogler-PigłowskaA, VydraN, et al., 2019. Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment. Sci Rep, 9:14394. ![]() [42]SongM, SandovalTA, ChaeCS, et al., 2018. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature, 562(7727):423-428. ![]() [43]Soto-PantojaDR, WilsonAS, ClearKYJ, et al., 2017. Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness. Oncotarget, 8(46):80545-80559. ![]() [44]SungH, FerlayJ, SiegelRL, et al., 2021. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3):209-249. ![]() [45]TakedaT, KomatsuM, ChiwakiF, et al., 2019. Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. Cell Death Dis, 10(12):876. ![]() [46]TangYB, ChenJ, LiJQ, et al., 2021. Pristimerin synergistically sensitizes conditionally reprogrammed patient derived-primary hepatocellular carcinoma cells to sorafenib through endoplasmic reticulum stress and ROS generation by modulating Akt/FoxO1/p27kip1 signaling pathway. Phytomedicine, 86:153563. ![]() [47]TianWJ, LeiNJ, ZhouJY, et al., 2022. Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis, 13:64. ![]() [48]WahbaJ, NatoliM, WhildingLM, et al., 2018. Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer. Cancer Immunol Immunother, 67(11):1753-1765. ![]() [49]WangJL, YangH, LiWJ, et al., 2015. Thioredoxin 1 upregulates FOXO1 transcriptional activity in drug resistance in ovarian cancer cells. Biochim Biophys Acta, 1852(3):395-405. ![]() [50]WangK, FengXJ, ZhengLZ, et al., 2021. TRPV4 is a prognostic biomarker that correlates with the immunosuppressive microenvironment and chemoresistance of anti-cancer drugs. Front Mol Biosci, 8:690500. ![]() [51]WangZQ, ZhouL, AnD, et al., 2019. TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice. Cell Death Dis, 10(6):386. ![]() [52]YangYL, ZhangY, LiDD, et al., 2020. RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2. Cell Death Differ, 27(3):1105-1118. ![]() [53]YeY, DaiQJ, LiSH, et al., 2021. A novel defined risk signature of the ferroptosis-related genes for predicting the prognosis of ovarian cancer. Front Mol Biosci, 8:645845. ![]() [54]ZhaiLL, QiaoPP, SunYS, et al., 2021. Upregulated HSPA2 predicts early relapse of pancreatic cancer after surgery. Gland Surg, 10(7):2140-2149. ![]() [55]ZhangB, NieXC, MiaoXX, et al., 2021. Development and verification of an immune-related gene pairs prognostic signature in ovarian cancer. J Cell Mol Med, 25(6):2918-2930. ![]() [56]ZhangH, ChenW, DuanCJ, et al., 2013. Overexpression of HSPA2 is correlated with poor prognosis in esophageal squamous cell carcinoma. World J Surg Oncol, 11:141. ![]() [57]ZhangYQ, WangYN, ZhaoGY, et al., 2022. FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway. J Clin Invest, 132(10):e151591. ![]() [58]ZhangYS, LiF, LiuLG, et al., 2019. Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells. BMC Cancer, 19:381. ![]() [59]ZhangZY, MouZZ, XuCY, et al., 2021. Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p/IGF2R regulation. Cell Death Dis, 12(8):778. ![]() [60]ZhaoLB, MaSJ, WangLCH, et al., 2021. A polygenic methylation prediction model associated with response to chemotherapy in epithelial ovarian cancer. Mol Ther Oncolytics, 20:545-555. ![]() [61]ZundellJA, FukumotoT, LinJH, et al., 2021. Targeting the IRE1α/XBP1 endoplasmic reticulum stress response pathway in ARID1A-mutant ovarian cancers. Cancer Res, 81(20):5325-5335. ![]() Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou
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