<p> 目的：旨在构建内质网应激基因相关风险模型预测宫颈癌患者的生存和分析不同风险组之间免疫原 性和免疫治疗的差异，为宫颈癌预后判断和精准治疗提供临床参考价值。 方法： 自 TCGA、GEO、 GTEx 数据库获取宫颈癌和正常宫颈的测序数据和相应的临床信息，Gene Card 数据库下载内质网应激相关基因，应用 R 软件行差异化、交集分析，确定内质网应激 (Endoplasmic reticulum stress, ERS)差异基因。采用 Cox 回归分析构建预后风险模型，根据模型 计算风险评分，绘制风险曲线、Kaplan-Meier(KM)生存曲线，应用受试者工作特征(receiver operating characteristic, ROC)曲线评估模型的效能，应用 Wilcoxon 秩和检验和卡方检验对高低 风险组临床特征分析，利用 GSE52903 数据集验证模型的适用性。采用单样本富集分析 (ssGSEA)确定与风险评分相关的 KEGG 通路，自肿瘤免疫组图谱(The Cancer Immunome Atlas，TCIA)获得 TCGA-CESE 免疫表型评分，分析免疫原性的差异，应用 TIDE 评分和 SubMap 算法预测宫颈癌患者免疫治疗的敏感性。应用 GSE52903 和 GSE7410 数据集验证 6 个 预后生物标志物的表达水平。用免疫组化法验证预后生物标志物在宫颈癌和癌旁组织的表达。 结果： 1. 本研究筛选出 42 个内质网应激相关共表达差异基因，单因素 Cox 分析得到 10 个 (DES,JUN,PLOD2,SLC2A1,TFRC,IL1B,SPP1,CXCL8,GJB2,DSG2)与预后相关的 ERS 相关基 因，多因素 Cox 分析确定 6 个 ERS 相关基因(DES,PLOD2, SPP1,CXCL8,GJB2,DSG2)构建最优 预后模型。K-M 生存曲线示高风险组生存率更低(P&lt;0.05)，ROC 曲线分析示 1 年 AUC 为 0.757，3 年 AUC 为 0.759，5 年 AUC 为 0.778。 2. 在 GSE52903 验证集验证风险模型，K-M 生存曲线分析示高风险组生存率更低(P=0.0039)， ROC 曲线分析示 1 年 AUC 为 0.816，3 年 AUC 为 0.657，5 年 AUC 为 0.634。 3. 临床特征相关分析示临床病理 T 分期、FIGO-stage 在高低风险组差异显著(P &lt;0.05)，单因素 Cox 分析示 Pathologic-T,FIGO-stage 和 Risk score 为独立预后因素(P &lt;0.05)，多因素 Cox 分析示 Risk score 为显著的独立预后因素(P &lt;0.05)。 4. ssGSEA 分析得到与风险评分正相关的 11KEGG 通路 (r＞0.35)，TNF 通路，IL-17 通路，HIF-1 通路，内质网中蛋白质加工通路、细胞衰老通路与免疫原性相关。 5. 低风险组 IPS-CTLA4、IPS-PD1-PD-L1-PD-L2、IPS- PD1-PD-L1-PD-L2-CTLA4 显著高于高风 险组(p&lt;0.05)，低风险组有更强的免疫原性表型。TIDE 评分分析免疫检测点抑制剂治疗敏感 性，高风险组(49/137, 35.8%)较低风险组(38/136, 27.9%)敏感(P =0.029)，SubMap 预测免疫治疗 的响应性，低分险组对 PD-1 疗法敏感(Nominal P&lt;0.05 )，高风险组对 CTLA4 疗法敏感 (Nominal P&lt;0.05 ) III 6. 验证 TCGA-CESE、GSE52903 和 GSE7410 数据集中 6 个预后风险因素标志物的表达，得到 DES、SPP1、PLOD2 在宫颈癌和正常组织中表达有差异，趋势一致。 7. 免疫组化染色法验证 ERS 相关基因 PLOD2、SPP1、DSG2、GJB2、DES、CLCX8 在宫颈癌组 织和癌旁组织的表达存在显著差异。PLOD2、SPP1、DSG2、GJB2、DES、CXCL8 在宫颈癌 组织中阳性表达(P＜0.05)，DES 在宫颈癌组织中阴性表达(P＜0.001)。 结论： 1. 本研究通过生物信息学方法构建了基于内质网应激相关基因预测宫颈癌预后的风险模型，发现 6 个与预后相关的基因，PLOD2、SPP1、DSG2、GJB2、CXCL8 为危险因素， DES 为保护性 因素。 2. 风险模型经其他数据集进行验证后，证实模型有效，能预测宫颈癌的预后，预测效能优于其他 临床特征，风险评分为宫颈癌预后的独立预后因素。 3. ERS 预后特征能预测宫颈癌患者的免疫原性和免疫治疗，风险基因也需要更多的功能分析来探 索其可能的免疫治疗机制和临床价值。</p>

<p> Objective: To construct an endoplasmic reticulum stress-related signature risk model to predict the survival of cervical cancer patients and analyze the differences in immunogenicity and immunotherapy between different risk groups to provide clinical reference value for prognosis determination and precise treatment of cervical cancer. Methods: RNA-Seq and corresponding clinical information for cervical cancer and normal cervix were obtained from TCGA, GEO, and GTEx databases, and endoplasmic reticulum stress-related genes were downloaded from Gene Card database, and R software was applied to differential and intersection analysis to identify ERS differential genes. The prognostic risk model was constructed using Cox regression analysis, risk scores were calculated based on the model, Kaplan-Meier (KM) survival curves, and receiver operating characteristic (ROC) curves were plotted to assess the efficacy of the model, and Wilcoxon test and chi-square test were applied to the clinical characteristics of the high and low risk groups were analyzed, and the applicability of the model was validated using the GSE5290 dataset. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to identify KEGG pathways associated with risk scores, TCGA-CESE immunophenoscores (IPS) were obtained from The Cancer Immunome Atlas (TCIA), differences in immunogenicity were analyzed, and the TIDE score and SubMap algorithm were applied to predict the sensitivity of immunotherapy in cervical cancer patients. The expression levels of six biomarkers were validated using the GSE52903 and GSE7410 datasets. The expression of prognostic biomarkers in cervical cancer and normal cervical tissue was verified by Immunohistochemical staining. Results: 1. In this study, 42 endoplasmic reticulum stress-related co-expression differential genes were screened, and 10 (DES, JUN, PLOD2, SLC2A1, TFRC, IL1B, SPP1, CXCL8, GJB2, DSG2) prognosis-related ERS genes were obtained by single-factor Cox analysis, and 6 ERS genes were identified by multi-factor Cox (DES, PLOD2, SPP1, CXCL8, GJB2, DSG2) to construct the optimal prognostic model. The K-M survival curves analysis showed lower survival in the high-risk group (p&lt;0.05), and the ROC curve validated the model, and 1-year AUC was 0.757, and 3-year AUC was 0.759, and 5-year AUC was 0.778. 2. The risk model was verified in the GSE52903 validation set. K-M survival curve analysis showed that the high-risk group had a lower survival (P=0.0039). ROC curve analysis showed that the1-year AUC V was 0.816, 3-year AUC was 0.657, and 5-year AUC was 0.634. 3. Correlation analysis of clinical characteristics showed significant differences in clinicopathologic T-stage and FIGO-stage in high and low risk groups (P&lt;0.05), Univariate analysis showed that Pathologic-T, FIGO-stage and Risk score were independent prognostic factors (p&lt;0.05), and multi-variate Cox analysis showed that Risk score was a significant independent prognostic (p&lt;0.05), and multivariate Cox analysis showed that Risk score was a significant independent prognostic factor (p&lt;0.05). 4. The ssGSEA analysis yielded positive correlations with risk scores for 11KEGG pathway (r &gt; 0.35), TNF pathway, IL-17 signaling pathway, HIF-1 pathway, protein processing in the endoplasmic reticulum pathway, and cellular senescence pathway associated with immunogenicity. IPS-CTLA4, IPS-PD1-PD-L1-PD-L2, and IPS- PD1-PD-L1-PD-L2-CTLA4 were significantly higher in the low-risk group than in the high-risk group (P&lt;0.05), and the low-risk group had a stronger immunogenic phenotype. The TIDE analysis of immune checkpoint inhibition treatment sensitivity was more sensitive (P=0.029) in the high-risk group (49/137, 35.8%) than in the low-risk group (38/136, 27.9%). 5. SubMap predicted responsiveness to immunotherapy, with the low-risk group sensitive to PD-1 therapy (Nominal P &lt;0.05) and the high-risk group sensitive to CTLA4 therapy (Nominal P&lt;0.05). 6. Validation of the expression of six prognostic risk factor markers in the TCGA-CESE, GSE52903, and GSE7410 datasets yielded differential expression of DES, SPP1, and PLOD2 in cervical cancer and normal tissues, with consistent trends. 7. Immunohistochemical staining confirmed that there were significant differences in the expression of ERS-related genes PLOD2, SPP1, DSG2, GJB2, CXCL8, and DES in cervical cancer tissues and adjacent cancerous tissues. PLOD2, SPP1, DSG2, GJB2, DES, and CXCL8 were positive expression in cancer tissues (P &lt; 0.05), and DES was negative expression in cancer tissues (P &lt; 0.001). Conclusion: 1. In this study, a prognostic risk model of cervical cancer was established based on endoplasmic reticulum stress-related genes by bioinformatics methods. Six prognostic genes were found, including PLOD2, SPP1, DSG2, GJB2, CXCL8 as risk factors and DES as protective factors. 2. The risk model was validated by other data sets and confirmed that the model was valid and could predict the prognosis of cervical cancer with better predictive efficacy than other clinical characteristics, and the risk score was an independent prognostic factor for the prognosis of cervical cancer. 3. ERS prognostic features predict immunogenicity and immunotherapy in patients with cervical cancer, and more functional analysis of risk genes is needed to explore their possible immunotherapeutic mechanisms and clinical value.</p>

<div>

[1]BALASUBRAMANIAM S D, BALAKRISHNAN V, OON C E, et al. Key Molecular Events in Cervical Cancer Development [J]. Medicina (Kaunas, Lithuania), 2019, 55(7) :384-396.&nbsp;</div>

<div>

[2]SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries [J]. CA: a cancer journal for clinicians, 2021, 71(3): 209-249.&nbsp;</div>

<div>

[3]CREE I A, WHITE V A, INDAVE B I, et al. Revising the WHO classification: female genital tract tumours [J]. Histopathology, 2020, 76(1): 151-156.&nbsp;</div>

<div>

[4]WATSON M, SARAIYA M, BENARD V, et al. Burden of cervical cancer in the United States, 1998-2003 [J]. Cancer, 2008, 113(10 Suppl): 2855-2864.&nbsp;</div>

<div>

[5]HU K, WANG W, LIU X, et al. Comparison of treatment outcomes between squamous cell carcinoma and adenocarcinoma of cervix after definitive radiotherapy or concurrent chemoradiotherapy [J]. Radiation oncology (London, England), 2018, 13(1): 249.&nbsp;</div>

<div>

[6]ABU-RUSTUM N R, YASHAR C M, BEAN S, et al. NCCN Guidelines Insights: Cervical Cancer, Version 1.2020 [J]. Journal of the National Comprehensive Cancer Network : JNCCN, 2020, 18(6): 660-666.&nbsp;</div>

<div>

[7]LANDONI F, COLOMBO A, MILANI R, et al. Randomized study between radical surgery and radiotherapy for the treatment of stage IB-IIA cervical cancer: 20-year update [J]. Journal of gynecologic oncology, 2017, 28(3): e34.&nbsp;</div>

<div>

[8]SARDAIN H, LAVOU&eacute; V, FOUCHER F, et al. [Curative pelvic exenteration for recurrent cervical carcinoma in the era of concurrent chemotherapy and radiation therapy. A systematic review] [J]. Journal de gynecologie, obstetrique et biologie de la reproduction, 2016, 45(4): 315-329.&nbsp;</div>

<div>

[9]LEWIS D R, SIEMBIDA E J, SEIBEL N L, et al. Survival outcomes for cancer types with the highest death rates for adolescents and young adults, 1975-2016 [J]. Cancer, 2021, 127(22): 4277-4286.&nbsp;</div>

<div>

[10]SANKARANARAYANAN R, SWAMINATHAN R, BRENNER H, et al. Cancer survival in Africa, Asia, and Central America: a population-based study [J]. The Lancet Oncology, 2010, 11(2): 165-173.&nbsp;</div>

<div>

[11]SMALL W, JR., BACON M A, BAJAJ A, et al. Cervical cancer: A global health crisis [J]. Cancer, 2017, 123(13): 2404-2412.&nbsp;</div>

<div>

[12]WAKATSUKI M, KATO S, KIYOHARA H, et al. The prognostic value of rectal invasion for stage IVA uterine cervical cancer treated with radiation therapy [J]. BMC cancer, 2016, 16: 244.&nbsp;</div>

<div>

[13]MONCAN M, MNICH K, BLOMME A, et al. Regulation of lipid metabolism by the unfolded protein response [J]. Journal of cellular and molecular medicine, 2021, 25(3): 1359-1370. [14]URRA H, DUFEY E, AVRIL T, et al. Endoplasmic Reticulum Stress and the Hallmarks of Cancer [J]. Trends in cancer, 2016, 2(5): 252-262.&nbsp;</div>

<div>

[15]YADAV R K, CHAE S W, KIM H R, et al. Endoplasmic reticulum stress and cancer [J]. Journal of cancer prevention, 2014, 19(2): 75-88.&nbsp;</div>

<div>

[16]RUTKOWSKI D T, KAUFMAN R J. A trip to the ER: coping with stress [J]. Trends in cell biology, 2004, 14(1): 20-28.&nbsp;</div>

<div>

[17]CHEN X, CUBILLOS-RUIZ J R. Endoplasmic reticulum stress signals in the tumour and its microenvironment [J]. Nature reviews Cancer, 2021, 21(2): 71-88.&nbsp;</div>

<div>

[18]MA Y, HENDERSHOT L M. ER chaperone functions during normal and stress conditions [J]. Journal of chemical neuroanatomy, 2004, 28(1-2): 51-65.&nbsp;</div>

<div>

[19]MAHADEVAN N R, RODVOLD J, SEPULVEDA H, et al. Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells [J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(16): 6561-6566. [</div>

<div>

20]CULLEN S J, FATEMIE S, LADIGES W. Breast tumor cells primed by endoplasmic reticulum stress remodel macrophage phenotype [J]. American journal of cancer research, 2013, 3(2): 196-210.&nbsp;</div>

<div>

[21]POMMIER A, ANAPARTHY N, MEMOS N, et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases [J]. Science (New York, NY), 2018, 7(15):360-385.&nbsp;</div>

<div>

[22]MAHADEVAN N R, ANUFREICHIK V, RODVOLD J J, et al. Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8? T cell priming [J]. PloS one, 2012, 7(12): e51845.&nbsp;</div>

<div>

[23]YAO X, TU Y, XU Y, et al. Endoplasmic reticulum stress-induced exosomal miR-27a-3p promotes immune escape in breast cancer via regulating PD-L1 expression in macrophages [J]. Journal of cellular and molecular medicine, 2020, 24(17): 9560-9573.&nbsp;</div>

<div>

[24]MOHAMED E, SIERRA R A, TRILLO-TINOCO J, et al. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling [J]. Immunity, 2020, 52(4): 668-682.&nbsp;</div>

<div>

[25]SONG M, SANDOVAL T A, CHAE C S, et al. IRE1&alpha;-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity [J]. Nature, 2018, 562(7727): 423-428. [26]LUO C, FAN W, JIANG Y, et al. Glucose-Related Protein 78 Expression and Its Effects on Cisplatin-Resistance in Cervical Cancer [J]. Medical science monitor : international medical journal of experimental and clinical research, 2018, 24: 2197-2209.&nbsp;</div>

<div>

[27]HE P Y, HOU Y H, YANG Y, et al. The anticancer effect of extract of medicinal mushroom Sanghuangprous vaninii against human cervical cancer cell via endoplasmic reticulum stress-mitochondrial apoptotic pathway [J]. Journal of ethnopharmacology, 2021, 279: 114345.&nbsp;</div>

<div>

[28]ZHANG Q, GUAN G, CHENG P, et al. Characterization of an endoplasmic reticulum stress-related signature to evaluate immune features and predict prognosis in glioma [J]. Journal of cellular and molecular medicine, 2021, 25(8): 3870-3884.&nbsp;</div>

<div>

[29]BLUM A, WANG P, ZENKLUSEN J C. SnapShot: TCGA-Analyzed Tumors [J]. Cell, 2018, 173(2): 530.&nbsp;</div>

<div>

[30]OKAYAMA H, SCHETTER A J, ISHIGAME T, et al. The expression of four genes as a prognostic classifier for stage I lung adenocarcinoma in 12 independent cohorts [J]. Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2014, 23(12): 2884-2894.&nbsp;</div>

<div>

[31]HE R, ZUO S. A Robust 8-Gene Prognostic Signature for Early-Stage Non-small Cell Lung Cancer [J]. Frontiers in oncology, 2019, 9: 693.&nbsp;</div>

<div>

[32]CHENG S H, HORNG C F, HUANG T T, et al. An Eighteen-Gene Classifier Predicts Locoregional Recurrence in Post-Mastectomy Breast Cancer Patients [J]. EBioMedicine, 2016, 5: 74-81.&nbsp;</div>

<div>

[33]QI L, YAO Y, ZHANG T, et al. A four-mRNA model to improve the prediction of breast cancer prognosis [J]. Gene, 2019, 721: 144100.&nbsp;</div>

<div>

[34]LIN P, GUO Y N, SHI L, et al. Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer [J]. Aging, 2019, 11(2): 480-500. [35]MA G, SONG G, ZOU X, et al. Circulating plasma microRNA signature for the diagnosis of cervical cancer [J]. Cancer biomarkers : section A of Disease markers, 2019, 26(4): 491-500.&nbsp;</div>

<div>

[36]NGUYEN N N Y, CHOI T G, KIM J, et al. A 70-Gene Signature for Predicting Treatment Outcome in Advanced-Stage Cervical Cancer [J]. Molecular therapy oncolytics, 2020, 19: 47-56.&nbsp;</div>

<div>

[37]XIE F, DONG D, DU N, et al. An 8?gene signature predicts the prognosis of cervical cancer following radiotherapy [J]. Molecular medicine reports, 2019, 20(4): 2990-3002. [38]CAI L, HU C, YU S, et al. Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer [J]. BMC cancer, 2020, 20(1): 1133.&nbsp;</div>

<div>

[39]LEE H, PALM J, GRIMES S M, et al. The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations [J]. Genome medicine, 2015, 7: 112.&nbsp;</div>

<div>

[40]LORENT M, GIRAL M, FOUCHER Y. Net time-dependent ROC curves: a solution for evaluating the accuracy of a marker to predict disease-related mortality [J]. Statistics in medicine, 2014, 33(14): 2379-2389.&nbsp;</div>

<div>

[41]HOLLECZEK B, BRENNER H. Model based period analysis of absolute and relative survival with R: data preparation, model fitting and derivation of survival estimates [J]. Computer methods and programs in biomedicine, 2013, 110(2): 192-202.&nbsp;</div>

<div>

[42]RASHID H O, YADAV R K, KIM H R, et al. ER stress: Autophagy induction, inhibition and selection [J]. Autophagy, 2015, 11(11): 1956-1977.&nbsp;</div>

<div>

[43]H&auml;NZELMANN S, CASTELO R, GUINNEY J. GSVA: gene set variation analysis for microarray and RNA-seq data [J]. BMC bioinformatics, 2013, 14: 7.&nbsp;</div>

<div>

[44]CHAROENTONG P, FINOTELLO F, ANGELOVA M, et al. Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade [J]. Cell reports, 2017, 18(1): 248-262.&nbsp;</div>

<div>

[45]JIANG P, GU S, PAN D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response [J]. Nature medicine, 2018, 24(10): 1550-1558.&nbsp;</div>

<div>

[46]HOSHIDA Y, BRUNET J P, TAMAYO P, et al. Subclass mapping: identifying common subtypes in independent disease data sets [J]. PloS one, 2007, 2(11): e1195.&nbsp;</div>

<div>

[47]KAGABU M, SHOJI T, MURAKAMI K, et al. Clinical efficacy of nedaplatin-based concurrent chemoradiotherapy for uterine cervical cancer: a Tohoku Gynecologic Cancer Unit Study [J]. International journal of clinical oncology, 2016, 21(4): 735-740.&nbsp;</div>

<div>

[48]WASSIE M, ARGAW Z, TSIGE Y, et al. Survival status and associated factors of death among cervical cancer patients attending at Tikur Anbesa Specialized Hospital, Addis Ababa, Ethiopia: a retrospective cohort study [J]. BMC cancer, 2019, 19(1): 1221.&nbsp;</div>

<div>

[49]MAO Y, DONG L, ZHENG Y, et al. Prediction of Recurrence in Cervical Cancer Using a Nine-lncRNA Signature [J]. Frontiers in genetics, 2019, 10: 284.&nbsp;</div>

<div>

[50]CHEN Q, QIU B, ZENG X, et al. Identification of a tumor microenvironment-related gene signature to improve the prediction of cervical cancer prognosis [J]. Cancer cell international, 2021, 21(1): 182.&nbsp;</div>

<div>

[51]PITT J M, V&eacute;TIZOU M, DAILL&egrave;RE R, et al. Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors [J]. Immunity, 2016, 44(6): 1255-1269.&nbsp;</div>

<div>

[52]SPRANGER S, GAJEWSKI T F. Tumor-intrinsic oncogene pathways mediating immune avoidance [J]. Oncoimmunology, 2016, 5(3): e1086862.&nbsp;</div>

<div>

[53]MAHONEY K M, RENNERT P D, FREEMAN G J. Combination cancer immunotherapy and new immunomodulatory targets [J]. Nature reviews Drug discovery, 2015, 14(8): 561-584.&nbsp;</div>

<div>

[54]CHUNG H C, ROS W, DELORD J P, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study [J]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 37(17): 1470-1478.&nbsp;</div>

<div>

[55]NAUMANN R W, HOLLEBECQUE A, MEYER T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial [J]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 37(31): 2825-2834.&nbsp;</div>

<div>

[56]LHEUREUX S, BUTLER M O, CLARKE B, et al. Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma [J]. JAMA oncology, 2018, 4(7): e173776.&nbsp;</div>

<div>

[57]LI G, WANG X, LIU G. PLOD2 Is a Potent Prognostic Marker and Associates with Immune Infiltration in Cervical Cancer [J]. BioMed research international, 2021, 2021: 5512340.&nbsp;</div>

<div>

[58]QIN S, LIAO Y, DU Q, et al. DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer [J]. Cancer cell international, 2020, 20: 206.&nbsp;</div>

<div>

[59]ZHAO K, MA Z, ZHANG W. Comprehensive Analysis to Identify SPP1 as a Prognostic Biomarker in Cervical Cancer [J]. Frontiers in genetics, 2021, 12: 732822.&nbsp;</div>

<div>

[60]ZHU T, GAO Y F, CHEN Y X, et al. Genome-scale analysis identifies GJB2 and ERO1LB as prognosis markers in patients with pancreatic cancer [J]. Oncotarget, 2017, 8(13): 21281-21289.&nbsp;</div>

<div>

[61]JIA L, LI F, SHAO M, et al. CXCL8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells [J]. Oncology letters, 2018, 15(1): 1350-1356.&nbsp;</div>

<div>

[62]GEIER R, ADLER S, RASHID G, et al. The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells [J]. The Prostate, 2010, 70(12): 1307-1312.&nbsp;</div>

<div>

[63]LEE A S. GRP78 induction in cancer: therapeutic and prognostic implications [J]. Cancer research, 2007, 67(8): 3496-3499.&nbsp;</div>

<div>

[64]ARAKI K, NAGATA K. Protein folding and quality control in the ER [J]. Cold Spring Harbor perspectives in biology, 2011, 3(11): a007526.&nbsp;</div>

<div>

[65]XU C, BAILLY-MAITRE B, REED J C. Endoplasmic reticulum stress: cell life and death decisions [J]. The Journal of clinical investigation, 2005, 115(10): 2656-2664.&nbsp;</div>

<div>

[66]HETZ C, CHEVET E, HARDING H P. Targeting the unfolded protein response in disease [J]. Nature reviews Drug discovery, 2013, 12(9): 703-719.&nbsp;</div>

<div>

[67]RUFO N, GARG A D, AGOSTINIS P. The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy [J]. Trends in cancer, 2017, 3(9): 643-658.&nbsp;</div>

<div>

[68]KIMATA Y, KOHNO K. Endoplasmic reticulum stress-sensing mechanisms in yeast and mammalian cells [J]. Current opinion in cell biology, 2011, 23(2): 135-142.&nbsp;</div>

<div>

[69]LIN J H, LI H, YASUMURA D, et al. IRE1 signaling affects cell fate during the unfolded protein response [J]. Science (New York, NY), 2007, 318(5852): 944-949.&nbsp;</div>

<div>

[70]CHEN Y, BRANDIZZI F. IRE1: ER stress sensor and cell fate executor [J]. Trends in cell biology, 2013, 23(11): 547-555.&nbsp;</div>

<div>

[71]PINCUS D, CHEVALIER M W, ARAG&oacute;N T, et al. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response [J]. PLoS biology, 2010, 8(7): e1000415.&nbsp;</div>

<div>

[72]MORI K, MA W, GETHING M J, et al. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus [J]. Cell, 1993, 74(4): 743-756.&nbsp;</div>

<div>

[73]WANG D, HOU C, CAO Y, et al. XBP1 activation enhances MANF expression via binding to endoplasmic reticulum stress response elements within MANF promoter region in hepatitis B [J]. The international journal of biochemistry &amp; cell biology, 2018, 99: 140-146.&nbsp;</div>

<div>

[74]BHARDWAJ M, LELI N M, KOUMENIS C, et al. Regulation of autophagy by canonical and non-canonical ER stress responses [J]. Seminars in cancer biology, 2020, 66: 116-128.&nbsp;</div>

<div>

[75]HOLLIEN J, LIN J H, LI H, et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells [J]. The Journal of cell biology, 2009, 186(3): 323-331.&nbsp;</div>

<div>

[76]HOLLIEN J, WEISSMAN J S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response [J]. Science (New York, NY), 2006, 313(5783): 104-107.&nbsp;</div>

<div>

[77]VOLMER R, VAN DER PLOEG K, RON D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains [J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(12): 4628-4633.&nbsp;</div>

<div>

[78]HARDING H P, ZHANG Y, RON D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase [J]. Nature, 1999, 397(6716): 271-274.&nbsp;</div>

<div>

[79]CHOY M S, YUSOFF P, LEE I C, et al. Structural and Functional Analysis of the GADD34:PP1 eIF2&alpha; Phosphatase [J]. Cell reports, 2015, 11(12): 1885-1891.&nbsp;</div>

<div>

[80]B&#39;CHIR W, MAURIN A C, CARRARO V, et al. The eIF2&alpha;/ATF4 pathway is essential for stress-induced autophagy gene expression [J]. Nucleic acids research, 2013, 41(16): 7683-7699.&nbsp;</div>

<div>

[81]HONG S H, LEE D H, LEE Y S, et al. Molecular crosstalk between ferroptosis and apoptosis: emerging role of ER stress-induced p53-independent PUMA expression [J]. Oncotarget, 2017, 8(70): 115164-115178.&nbsp;</div>

<div>

[82]CORRELL R N, GRIMES K M, PRASAD V, et al. Overlapping and differential functions of ATF6&alpha; versus ATF6&beta; in the mouse heart [J]. Scientific reports, 2019, 9(1): 2059.&nbsp;</div>

<div>

[83]SHEN J, CHEN X, HENDERSHOT L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals [J]. Developmental cell, 2002, 3(1): 99-111.&nbsp;</div>

<div>

[84]LEE K, TIRASOPHON W, SHEN X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response [J]. Genes &amp; development, 2002, 16(4): 452-466.&nbsp;</div>

<div>

[85]LEE A H, IWAKOSHI N N, GLIMCHER L H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response [J]. Molecular and cellular biology, 2003, 23(21): 7448-7459.&nbsp;</div>

<div>

[86]HILLARY R F, FITZGERALD U. A lifetime of stress: ATF6 in development and homeostasis [J]. Journal of biomedical science, 2018, 25(1): 48.&nbsp;</div>

<div>

[87]SCHEWE D M, AGUIRRE-GHISO J A. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo [J]. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(30): 10519-10524.&nbsp;</div>

<div>

[88]KOUMENIS C, WOUTERS B G. &quot;Translating&quot; tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways [J]. Molecular cancer research : MCR, 2006, 4(7): 423-436.&nbsp;</div>

<div>

[89]KORITZINSKY M, LEVITIN F, VAN DEN BEUCKEN T, et al. Two phases of disulfide bond formation have differing requirements for oxygen [J]. The Journal of cell biology, 2013, 203(4): 615-627.&nbsp;</div>

<div>

[90]MAY D, ITIN A, GAL O, et al. Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer [J]. Oncogene, 2005, 24(6): 1011-1020.&nbsp;</div>

<div>

[91]YOUNG R M, ACKERMAN D, QUINN Z L, et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress [J]. Genes &amp; development, 2013, 27(10): 1115-1131.&nbsp;</div>

<div>

[92]ROMERO-RAMIREZ L, CAO H, NELSON D, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth [J]. Cancer research, 2004, 64(17): 5943-5947.&nbsp;</div>

<div>

[93]DENZEL M S, ANTEBI A. Hexosamine pathway and (ER) protein quality control [J]. Current opinion in cell biology, 2015, 33: 14-18.&nbsp;</div>

<div>

[94]DOMBLIDES C, LARTIGUE L, FAUSTIN B. Metabolic Stress in the Immune Function of T Cells, Macrophages and Dendritic Cells [J]. Cells, 2018, 7(7):68-87&nbsp;</div>

<div>

[95]BRAAKMAN I, BULLEID N J. Protein folding and modification in the mammalian endoplasmic reticulum [J]. Annual review of biochemistry, 2011, 80: 71-99.&nbsp;</div>

<div>

[96]MOORE C E, OMIKOREDE O, GOMEZ E, et al. PERK activation at low glucose concentration is mediated by SERCA pump inhibition and confers preemptive cytoprotection to pancreatic &beta;-cells [J]. Molecular endocrinology (Baltimore, Md), 2011, 25(2): 315-326.&nbsp;</div>

<div>

[97]PAKOS-ZEBRUCKA K, KORYGA I, MNICH K, et al. The integrated stress response [J]. EMBO reports, 2016, 17(10): 1374-1395.&nbsp;</div>

<div>

[98]WEI Y, WANG D, TOPCZEWSKI F, et al. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells [J]. American journal of physiology Endocrinology and metabolism, 2006, 291(2): E275-281.&nbsp;</div>

<div>

[99]ZHANG X, CHEN M, ZOU P, et al. Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells [J]. BMC cancer, 2015, 15: 866.&nbsp;</div>

<div>

[100]IURLARO R, MU&ntilde;OZ-PINEDO C. Cell death induced by endoplasmic reticulum stress [J]. The FEBS journal, 2016, 283(14): 2640-2652.&nbsp;</div>

<div>

[101]ZHANG Z, ZHANG L, ZHOU L, et al. Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress [J]. Redox biology, 2019, 25: 101047.&nbsp;</div>

<div>

[102]MA J, LIU J, LU C, et al. Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells [J]. Cancer cell international, 2015, 15: 78.&nbsp;</div>

<div>

[103]GERAGHTY P, WALLACE A, D&#39;ARMIENTO J M. Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process [J]. International journal of chronic obstructive pulmonary disease, 2011, 6: 309-319.&nbsp;</div>

<div>

[104]SHIMIZU Y, HENDERSHOT L M. Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species [J]. Antioxidants &amp; redox signaling, 2009, 11(9): 2317-2331.&nbsp;</div>

<div>

[105]ZHANG J, PAVLOVA N N, THOMPSON C B. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine [J]. The EMBO journal, 2017, 36(10): 1302-1315. [106]LIOU G Y, STORZ P. Reactive oxygen species in cancer [J]. Free radical research, 2010, 44(5): 479-496.&nbsp;</div>

<div>

[107]CUBILLOS-RUIZ J R, SILBERMAN P C, RUTKOWSKI M R, et al. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis [J]. Cell, 2015, 161(7): 1527-1538.&nbsp;</div>

<div>

[108]VLADYKOVSKAYA E, SITHU S D, HABERZETTL P, et al. Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress [J]. The Journal of biological chemistry, 2012, 287(14): 11398-11409.&nbsp;</div>

<div>

[109]MAEYASHIKI C, MELHEM H, HERING L, et al. Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1&alpha;/JNK Pathway in an Intestinal Epithelial Cell Model [J]. Scientific reports, 2020, 10(1): 1438.&nbsp;</div>

<div>

[110]SCHLEICHER S M, MORETTI L, VARKI V, et al. Progress in the unraveling of the endoplasmic reticulum stress/autophagy pathway and cancer: implications for future therapeutic approaches [J]. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2010, 13(3): 79-86.&nbsp;</div>

<div>

[111]KIM C, KIM B. Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review [J]. Nutrients, 2018, 10(8):1021-1049.&nbsp;</div>

<div>

[112]WANG M, KAUFMAN R J. The impact of the endoplasmic reticulum protein-folding environment on cancer development [J]. Nature reviews Cancer, 2014, 14(9): 581-597.&nbsp;</div>

<div>

[113]LU M, LAWRENCE D A, MARSTERS S, et al. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis [J]. Science (New York, NY), 2014, 345(6192): 98-101.&nbsp;</div>

<div>

[114]URRA H, DUFEY E, LISBONA F, et al. When ER stress reaches a dead end [J]. Biochimica et biophysica acta, 2013, 1833(12): 3507-3517.&nbsp;</div>

<div>

[115]TABAS I, RON D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress [J]. Nature cell biology, 2011, 13(3): 184-190.&nbsp;</div>

<div>

[116]CHEN L, XU S, LIU L, et al. Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP [J]. Cell death &amp; disease, 2014, 5(5): e1219.&nbsp;</div>

<div>

[117]UPTON J P, WANG L, HAN D, et al. IRE1&alpha; cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2 [J]. Science (New York, NY), 2012, 338(6108): 818-822.&nbsp;</div>

<div>

[118]ROZPEDEK W, PYTEL D, MUCHA B, et al. The Role of the PERK/eIF2&alpha;/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress [J]. Current molecular medicine, 2016, 16(6): 533-544.&nbsp;</div>

<div>

[119]MA Y, HENDERSHOT L M. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress [J]. The Journal of biological chemistry, 2003, 278(37): 34864-34873.&nbsp;</div>

<div>

[120]JAUD M, PHILIPPE C, DI BELLA D, et al. Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers [J]. Cells, 2020, 9(3) :540-567.&nbsp;</div>

<div>

[121]LIU D D, ZHANG B L, YANG J B, et al. Celastrol ameliorates endoplasmic stress-mediated apoptosis of osteoarthritis via regulating ATF-6/CHOP signalling pathway [J]. The Journal of pharmacy and pharmacology, 2020, 72(6): 826-835.&nbsp;</div>

<div>

[122]TANG Y H, YUE Z S, ZHENG W J, et al. 4-Phenylbutyric acid presents therapeutic effect on osteoarthritis via inhibiting cell apoptosis and inflammatory response induced by endoplasmic reticulum stress [J]. Biotechnology and applied biochemistry, 2018, 65(4): 540-546.&nbsp;</div>

<div>

[123]YANG Y, SUN M, SHAN Y, et al. Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats [J]. Reproductive sciences (Thousand Oaks, Calif), 2015, 22(5): 572-584.&nbsp;</div>

<div>

[124]ROUSCHOP K M, VAN DEN BEUCKEN T, DUBOIS L, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5 [J]. The Journal of clinical investigation, 2010, 120(1): 127-141.&nbsp;</div>

<div>

[125]ZHANG Z, GAO W, ZHOU L, et al. Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy [J]. Theranostics, 2019, 9(17): 4878-4892. [126]FUCIKOVA J, KEPP O, KASIKOVA L, et al. Detection of immunogenic cell death and its relevance for cancer therapy [J]. Cell death &amp; disease, 2020, 11(11): 1013.&nbsp;</div>

<div>

[127]RADOGNA F, DIEDERICH M. Stress-induced cellular responses in immunogenic cell death: Implications for cancer immunotherapy [J]. Biochemical pharmacology, 2018, 153: 12-23. [128]OBEID M, TESNIERE A, GHIRINGHELLI F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death [J]. Nature medicine, 2007, 13(1): 54-61.&nbsp;</div>

<div>

[129]ZITVOGEL L, KEPP O, SENOVILLA L, et al. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway [J]. Clinical cancer research : an official journal of the American Association for Cancer Research, 2010, 16(12): 3100-3104.&nbsp;</div>

<div>

[130]OBACZ J, AVRIL T, RUBIO-PATI&ntilde;O C, et al. Regulation of tumor-stroma interactions by the unfolded protein response [J]. The FEBS journal, 2019, 286(2): 279-296.&nbsp;</div>

<div>

[131]PANARETAKIS T, KEPP O, BROCKMEIER U, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death [J]. The EMBO journal, 2009, 28(5): 578-590.&nbsp;</div>

<div>

[132]LI W, YANG J, LUO L, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death [J]. Nature communications, 2019, 10(1): 3349.&nbsp;</div>

<div>

[133]BINET F, SAPIEHA P. ER Stress and Angiogenesis [J]. Cell metabolism, 2015, 22(4): 560-575.&nbsp;</div>

<div>

[134]GARG A D, MAES H, VAN VLIET A R, et al. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress [J]. Molecular &amp; cellular oncology, 2015, 2(1): e975089.&nbsp;</div>

<div>

[135]CHEN X, KANG R, KROEMER G, et al. Broadening horizons: the role of ferroptosis in cancer [J]. Nature reviews Clinical oncology, 2021, 18(5): 280-296.&nbsp;</div>

<div>

[136]FU X, CUI J, MENG X, et al. Endoplasmic reticulum stress, cell death and tumor: Association between endoplasmic reticulum stress and the apoptosis pathway in tumors (Review) [J]. Oncology reports, 2021, 45(3): 801-808.&nbsp;</div>

<div>

[137]DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death [J]. Cell, 2012, 149(5): 1060-1072.&nbsp;</div>

<div>

[138]LEE Y S, LEE D H, CHOUDRY H A, et al. Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis [J]. Molecular cancer research : MCR, 2018, 16(7): 1073-1076.&nbsp;</div>

<div>

[139]SU N, KILBERG M S. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene [J]. The Journal of biological chemistry, 2008, 283(50): 35106-35117.&nbsp;</div>

<div>

[140]GHOSH A P, KLOCKE B J, BALLESTAS M E, et al. CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress [J]. PloS one, 2012, 7(6): e39586.&nbsp;</div>

<div>

[141]QIN J, SONG G, WANG Y, et al. Ultrasound irradiation inhibits proliferation of cervical cancer cells by initiating endoplasmic reticulum stress-mediated apoptosis and triggering phosphorylation of JNK [J]. Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 2021, 30(5): 545-554.&nbsp;</div>

<div>

[142]TAGUCHI Y, HORIUCHI Y, KANO F, et al. Novel prosurvival function of Yip1A in human cervical cancer cells: constitutive activation of the IRE1 and PERK pathways of the unfolded protein response [J]. Cell death &amp; disease, 2017, 8(3): e2718.&nbsp;</div>

<div>

[143]GUO J, YANG Z, YANG X, et al. miR-346 functions as a pro-survival factor under ER stress by activating mitophagy [J]. Cancer letters, 2018, 413: 69-81.&nbsp;</div>

<div>

[144]LI X M, LIU J, PAN F F, et al. Quercetin and aconitine synergistically induces the human cervical carcinoma HeLa cell apoptosis via endoplasmic reticulum (ER) stress pathway [J]. PloS one, 2018, 13(1): e0191062.&nbsp;</div>

<div>

[145]OU Y, XU S, ZHU D, et al. Molecular mechanisms of exopolysaccharide from Aphanothece halaphytica (EPSAH) induced apoptosis in HeLa cells [J]. PloS one, 2014, 9(1): e87223. [146]TSAI T L, WANG H C, HUNG C H, et al. Wheat germ agglutinin-induced paraptosis-like cell death and protective autophagy is mediated by autophagy-linked FYVE inhibition [J]. Oncotarget, 2017, 8(53): 91209-91222.&nbsp;</div>

<div>

[147]HUANG T C, CHEN J Y. Proteomic analysis reveals that pardaxin triggers apoptotic signaling pathways in human cervical carcinoma HeLa cells: cross talk among the UPR, c-Jun and ROS [J]. Carcinogenesis, 2013, 34(8): 1833-1842.</div>