Establishment of a prognostic prediction model for pancreatic cancer based on endoplasmic reticulum stress-related genes

Shengnan LYU; Xinyu PENG; Jian ZHANG; Huan LIU; Feng WEI

doi:10.3969/j.issn.1001-5256.2023.12.021

Volume 39 Issue 12

Dec. 2023

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Article Navigation > Journal of Clinical Hepatology > 2023 > 39(12): 2894-2900

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Establishment of a prognostic prediction model for pancreatic cancer based on endoplasmic reticulum stress-related genes

DOI: 10.3969/j.issn.1001-5256.2023.12.021

Department of Hepatobiliary and Pancreatic Surgery，General Surgery Center，The First Hospital of Jilin University，Changchun 130021，China

Research funding:

National Natural Science Foundation of China (81972273);

National Natural Science Foundation of China (82273276)

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Corresponding author: FENG Wei， wei_feng@jlu.edu.cn （ORCID： 0000-0001-8451-4516）
Received Date: 2023-09-10
Accepted Date: 2023-10-09
Published Date: 2023-12-12

Abstract

Abstract

Objective To investigate the role of endoplasmic reticulum stress genes in the prognosis of pancreatic cancer， and to establish a prognostic prediction model based on the prognostic markers for pancreatic cancer. Methods Transcriptome sequencing data were downloaded from TCGA and GTEx databases， and MsigDB website was used to obtain endoplasmic reticulum stress genes. A univariate Cox regression analysis was performed to obtain the genes associated with the prognosis of pancreatic cancer， and a consensus clustering analysis was used to construct the molecular typing of pancreatic cancer， while the differentially expressed genes between the two subgroups were obtained. A Lasso regression analysis was used to obtain the core genes associated with the prognosis of pancreatic cancer， which were used to construct a prognostic prediction model for pancreatic cancer. Related datasets were obtained from the GEO database to validate the predictive performance of the model. The CIBERSORT analysis was used to investigate the correlation between risk score and immune infiltration. Quantitative real-time PCR was used to measure the expression of genes in pancreatic cancer tissue and cell lines. The independent-samples t test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between groups. Survival was compared using Log-rank test. The predictive value of the model was evaluated by evaluating the area under the ROC curve. Results The endoplasmic reticulum stress genes CEBPB， MARCKS， PMAIP1， and UBXN10 were independent risk factors for the prognosis of pancreatic cancer， and based on the expression characteristics of these genes， the TCGA pancreatic cancer cohort was divided into two subgroups， i.e.， cluster A and cluster B， while the cluster A patients had a significantly shorter overall survival time than the cluster B patients （P<0.01）. The Lasso regression analysis obtained 5 core genes from the differentially expressed genes affecting the prognosis of pancreatic cancer， and the risk scoring system was established as risk score=0.156×CDA+0.135×AHNAK2+0.020×RHOV+0.095×LY6D+0.054×SPRR1B. The ROC curve analysis showed that this model had good overall predictive performance， with the area under the ROC curve of 0.731 at 1 year， 0.712 at 3 years， and 0.686 at 5 years， and the low-risk group based on this model had a significantly longer overall survival time than the high-risk group （χ²=11.733， P=0.001）. The model showed good predictive performance in the external dataset GSE57495. Quantitative real-time PCR results showed that the expression levels of CDA， AHNAK2， RHOV， LY6D， and SPRR1B in 40 pancreatic cancer tissue samples were significantly upregulated compared with those in normal adjacent tissue samples （t=2.529， 2.458， 3.314， 3.583， and 5.082， all P<0.05）. Conclusion The expression characteristics of CDA， AHNAK2， RHOV， LY6D， and SPRR1B can be used to predict the prognosis of pancreatic cancer， and the high expression levels of these genes are associated with the poor prognosis of pancreatic cancer patients.
- Pancreatic Neoplasms,
- Endoplasmic Reticulum Stress,
- Prognosis,
- Risk Factors

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References(21)

References

[1]	SPRINGFELD C, FERRONE CR, KATZ MHG, et al. Neoadjuvant therapy for pancreatic cancer[J]. Nat Rev Clin Oncol, 2023, 20( 5): 318- 337. DOI: 10.1038/s41571-023-00746-1.
[2]	CUBILLOS-RUIZ JR, BETTIGOLE SE, GLIMCHER LH. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer[J]. Cell, 2017, 168( 4): 692- 706. DOI: 10.1016/j.cell.2016.12.004.
[3]	RAINES LN, ZHAO HX, WANG YZ, et al. PERK is a critical metabolic hub for immunosuppressive function in macrophages[J]. Nat Immunol, 2022, 23( 3): 431- 445. DOI: 10.1038/s41590-022-01145-x.
[4]	CHEN X, CUBILLOS-RUIZ JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment[J]. Nat Rev Cancer, 2021, 21( 2): 71- 88. DOI: 10.1038/s41568-020-00312-2.
[5]	SAMANTA S, YANG SH, DEBNATH B, et al. The hydroxyquinoline analogue YUM70 inhibits GRP78 to induce ER stress-mediated apoptosis in pancreatic cancer[J]. Cancer Res, 2021, 81( 7): 1883- 1895. DOI: 10.1158/0008-5472.CAN-20-1540.
[6]	SIEGEL RL, MILLER KD, WAGLE NS, et al. Cancer statistics, 2023[J]. CA A Cancer J Clinicians, 2023, 73( 1): 17- 48. DOI: 10.3322/caac.21763.
[7]	WOOD LD, CANTO MI, JAFFEE EM, et al. Pancreatic cancer: Pathogenesis, screening, diagnosis, and treatment[J]. Gastroenterology, 2022, 163( 2): 386- 402.e1. DOI: 10.1053/j.gastro.2022.03.056.
[8]	CHANG XD, LI HY, CHEN J, et al. The role of lncRNA GAS5 in cell apoptosis, migration and invasion of AsPC-1 pancreatic cancer cell[J]. Clin J Med Offic, 2022, 50( 6): 599- 602. DOI: 10.16680/j.1671-3826.2022.06.15. 常旭东, 李宏宇, 陈江, 等. 长链非编码RNA GAS5对胰腺癌AsPC-1细胞凋亡、迁移及侵袭能力调控作用[J]. 临床军医杂志, 2022, 50( 6): 599- 602. DOI: 10.16680/j.1671-3826. 2022.06.15.
[9]	TEMPERO MA. NCCN guidelines updates: Pancreatic cancer[J]. J Natl Compr Canc Netw, 2019, 17( 5.5): 603- 605. DOI: 10.6004/jnccn.2019.5007.
[10]	ZHANG TP, LIU YZ, REN B. Current status and challenges of total neoadjuvant therapy for pancreatic cancer[J]. Chin J Dig Surg, 2022, 21( 4): 461- 464. DOI: 10.3760/cma.j.cn115610-20220320-00141. 张太平, 刘悦泽, 任博. 胰腺癌全程新辅助治疗的现状及挑战[J]. 中华消化外科杂志, 2022, 21( 4): 461- 464. DOI: 10.3760/cma.j.cn115610-20220320-00141.
[11]	CHEN BT, MAO XH. Clinical research advance in immunotherapy of pancreatic cancer[J]. Chin J Dig Surg, 2023, 22( 5): 610- 615. DOI: 10.3760/cma.j.cn115610-20230407-00158. 陈博滔, 毛先海. 胰腺癌免疫治疗临床研究进展[J]. 中华消化外科杂志, 2023, 22( 5): 610- 615. DOI: 10.3760/cma.j.cn115610-20230407-00158.
[12]	LI ZX, GE Y, DONG J, et al. BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation[J]. Gastroenterology, 2022, 162( 4): 1256- 1271.e14. DOI: 10.1053/j.gastro.2021.12.249.
[13]	ZHANG JF, YANG JY, LIN CY, et al. Endoplasmic reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in pancreatic cancer[J]. Theranostics, 2020, 10( 18): 8400- 8414. DOI: 10.7150/thno.45124.
[14]	LIU Z, LIU GL, HA DP, et al. ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator[J]. Proc Natl Acad Sci USA, 2023, 120( 31): e2303448120. DOI: 10.1073/pnas.2303448120.
[15]	NIU ZY, WANG MY, ZHOU L, et al. Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer[J]. Sci Rep, 2015, 5: 16067. DOI: 10.1038/srep16067.
[16]	MARTINEZ-USEROS J, GEORGIEV-HRISTOV T, BORRERO- PALACIOS A, et al. Identification of poor-outcome biliopancreatic carcinoma patients with two-marker signature based on ATF6α and p-p38 STARD compliant[J]. Medicine, 2015, 94( 45): e1972. DOI: 10.1097/MD.0000000000001972.
[17]	VANDE VOORDE J, SABUNCUOĞLU S, NOPPEN S, et al. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine[J]. J Biol Chem, 2014, 289( 19): 13054- 13065. DOI: 10.1074/jbc.M114.558924.
[18]	GELLER LT, BARZILY-ROKNI M, DANINO T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine[J]. Science, 2017, 357( 6356): 1156- 1160. DOI: 10.1126/science.aah5043.
[19]	LU D, WANG JX, SHI XY, et al. AHNAK2 is a potential prognostic biomarker in patients with PDAC[J]. Oncotarget, 2017, 8( 19): 31775- 31784. DOI: 10.18632/oncotarget.15990.
[20]	WANG XT, DOU XL, REN XX, et al. A ductal-cell-related risk model integrating single-cell and bulk sequencing data predicts the prognosis of patients with pancreatic adenocarcinoma[J]. Front Genet, 2021, 12: 763636. DOI: 10.3389/fgene.2021.763636.
[21]	LIU Y, SHAO ML, WU Y, et al. Role for the endoplasmic reticulum stress sensor IRE1alpha in liver regenerative responses[J]. J Hepatol, 2015, 62( 3): 590- 598. DOI: 10.1016/j.jhep.2014.10.022.

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