ORIGINAL ARTICLE
Single-minded homolog 2 as a potential prognostic signature and assessment of its correlation with immune cell infiltration in pancreatic cancer
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1
Operating Room of Anesthesia Surgery Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
2
Institute of Digestive Surgery, and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
3
Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
4
Department of Pancreatic Surgery, Center of Excellence for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Submission date: 2023-07-30
Final revision date: 2023-10-14
Acceptance date: 2023-11-15
Publication date: 2024-02-01
Corresponding author
Huimin Lu
Huimin Lu
Department of Pancreatic Surgery
Center of Excellence for Pancreatitis
West China Hospital, Sichuan University
Chengdu, Sichuan, 610041, China
Pol J Pathol 2023;74(4):232-247
KEYWORDS
TOPICS
ABSTRACT
Single-minded homolog 2 (SIM2) has been identified as a potential contributor to the development of solid tumors. Despite this, there is a lack of comprehensive research regarding its biological role and underlying mechanism within pancreatic cancer (PC), as well as its prognostic impact.
This study systematically evaluated the expression level and clinical significance of SIM2 in patients with PC using various databases, including The Cancer Genome Atlas, KM Plotter, and gene expression profiling interactive analysis. To investigate the relationship between SIM2 expression and immune cell infiltration, we conducted ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) analyses.
Single-minded homolog 2 was up-regulated in patients with PC. Pancreatic cancer patients with higher SIM2 expression had poorer overall survival rates. Gene set enrichment analysis results suggested that SIM2 may have a significant impact on the progression of PC and the regulation of immune responses. According to the ssGSEA algorithm, SIM2 has a negative correlation with the levels of infiltrating TFH, mast cells, and pDC.
Our study demonstrated that SIM2 serves as a biomarker, and is associated with both prognosis and immune infiltration in PC. This provides a solid foundation for future investigations into the precise role of SIM2 in the carcinogenesis and progression of PC.
REFERENCES (34)
1.
McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018; 24: 4846-4861.
2.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74: 2913-2921.
3.
Xu JW, Wang L, Cheng YG, et al. Immunotherapy for pancreatic cancer: a long and hopeful journey. Cancer Lett 2018; 425: 143-151.
4.
Lai E, Puzzoni M, Ziranu P, et al. New therapeutic targets in pancreatic cancer. Cancer Treat Rev 2019; 81: 101926.
5.
Button EL, Rossi JJ, McDougal DP, et al. Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes. Biochem J 2022; 479: 1441-1454.
6.
Ema M, Ikegami S, Hosoya T, et al. Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down’s syndrome. Hum Mol Genet 1999; 8: 1409-1415.
7.
Chatterjee A, Dutta S, Mukherjee S, et al. Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies. BMC Med Genet 2013; 14: 12.
8.
Woods S, Farrall A, Procko C, Whitelaw ML. The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence. Nucleic Acids Res 2008; 36: 3716-3727.
9.
Chen KJ, Lizaso A, Lee YH. SIM2 maintains innate host defense of the small intestine. American journal of physiology. Gastrointest Liv Physiol 2014; 307: G1044-56.
10.
He Q, Li G, Su Y, et al. Single minded 2-s (SIM2-s) gene is expressed in human GBM cells and involved in GBM invasion. Cancer Biol Ther 2010; 9: 430-436.
11.
Lu B, Asara JM, Sanda MG, Arredouani MS. The role of the transcription factor SIM2 in prostate cancer. PloS One 2011; 6: e28837.
12.
Halvorsen OJ, Rostad K, Øyan AM, et al. Increased expression of SIM2-s protein is a novel marker of aggressive prostate cancer. Clin Cancer Res 2007; 13: 892-897.
13.
Bartha Á, Győrffy B. TNMplot.com: a web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci 2021; 22: 2622.
14.
Tang Z, Li C, Kang B, Gao G, Li C. Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45: W98-w102.
15.
Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform 2011; 12: 77.
16.
Jin X, Liu G, Zhang X, Du N. Long noncoding RNA TMEM75 promotes colorectal cancer progression by activation of SIM2. Gene 2018; 675: 80-87.
17.
Tamaoki M, Komatsuzaki R, Komatsu M, et al. Multiple roles of single-minded 2 in esophageal squamous cell carcinoma and its clinical implications. Cancer Sci 2018; 109: 1121-1134.
18.
Nakamura K, Komatsu M, Chiwaki F, et al. SIM2l attenuates resistance to hypoxia and tumor growth by transcriptional suppression of HIF1A in uterine cervical squamous cell carcinoma. Sci Rep 2017; 7: 14574.
19.
Padoan A, Plebani M, Basso D. Inflammation and pancreatic cancer: focus on metabolism, cytokines, and immunity. Int J Mol Sci 2019; 20: 676.
20.
Shadhu K, Xi C. Inflammation and pancreatic cancer: an updated review. Saudi J Gastroenterol 2019; 25: 3-13.
21.
Scribner KC, Wellberg EA, Metz RP, Porter WW. Singleminded-2s (Sim2s) promotes delayed involution of the mouse mammary gland through suppression of Stat3 and NF-B. Mol Endocrinol (Baltimore, Md.) 2011; 25: 635-644.
22.
Wyatt GL, Crump LS, Young CM, et al. Cross-talk between SIM2s and NF-B regulates cyclooxygenase 2 expression in breast cancer. Breast Cancer Res 2019; 21: 131.
23.
Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018; 24: 541-550.
24.
Mao X, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer 2021; 20: 131.
25.
Ren B, Cui M, Yang G, et al. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer 2018; 17: 108.
26.
Tahkola K, Mecklin JP, Wirta EV, et al. High immune cell score predicts improved survival in pancreatic cancer. Virchows Arch 2018; 472: 653-665.
27.
Ino Y, Yamazaki-Itoh R, Shimada K, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 2013; 108: 914-923.
28.
Liu J, Xie X, Xuan C, et al. High-density infiltration of v- domain immunoglobulin suppressor of t-cell activation up-regulated immune cells in human pancreatic cancer. Pancreas 2018; 47: 725-731.
29.
Hegde S, Krisnawan VE, Herzog BH, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 2020; 37: 289-307.e9.
30.
Yang J, Zhang Q, Wang J, et al. Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy. EBioMedicine 2022; 78: 103958.
31.
Hoshikawa M, Aoki T, Matsushita H, et al. NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer. Biochem Biophys Res Commun 2018; 495: 2058-2065.
32.
Hirooka S, Yanagimoto H, Satoi S, et al. The role of circulating dendritic cells in patients with unresectable pancreatic cancer. Anticancer Res 2011; 31: 3827-3834.
33.
Wang Y, Fang T, Huang L, et al. Neutrophils infiltrating pancreatic ductal adenocarcinoma indicate higher malignancy and worse prognosis. Biochem Biophys Res Commun 2018; 501: 313-319.
34.
Ohkuma R, Kubota Y, Horiike A, et al. The prognostic impact of eosinophils and the eosinophil-to-lymphocyte ratio on survival outcomes in stage II resectable pancreatic cancer. Pancreas 2021; 50: 167-175.