CRABP2 (Cellular Retinoic Acid Binding Protein 2D): A Novel Biomarker for the Diagnosis and Prognosis Involved in Immune Infiltration of Lung Adenocarcinoma

Overview

Journal J Cancer

Specialty Oncology

Date 2025 Feb 24

PMID 39991584

Authors

DaXia Cai

Feng Tian

Dengke Zhang

Jianfei Tu

Yonghui Wang

Affiliations

Soon will be listed here.

Abstract

Overexpressed CRABP2 (Cellula Retinoi Aci Bindin Protei 2D) can promote progression of various tumors. However, there are few comprehensive analysis studies on CRABP2 in lung adenocarcinoma (LUAD). Several large public databases and online analysis tools such as TCGA, GEO, GEPIA2, UALCAN, Kaplan Meier plotter, LinkedOmics, TIMER, CCLE and Metascape were used for big data mining analysis. RNA interference technology, CCK8 assay, flow cytometry and apoptosis detection, and western blot were used for experiments. The study revealed that the expression level of CRABP2 in plasma were higher (mean level 31.6587 ±13.8541 ng/mL vs. 13.9328 ± 5.5805 ng/mL, <0.0001) in patients with early stage (stage IA) LUAD compared to the control group based on analysis of 640 LUAD patients and 640 matched healthy control plasma samples from Lishui Central Hospital. Receiver Operating Characteristic curve showed that CRABP2 had certain accuracy in predicting early LUAD, with a sensitivity of 70.98%, a specificity of 94.53%, a cut-off value of 0.6551 ng/mL, and an Area Under the Curve of 0.839 (95%CI: 0.817 - 0.859, <0.0001). Compared with normal lung tissue, CRABP2 was significantly overexpressed in LUAD (<0.05). High CRABP2 expression in LUAD predicts poor prognosis both in Overall Survival (95%CI: 1.04-1.46, HR:1.23, =0.018) and FP (First Progression, 95%CI: 1.10-1.65, HR = 1.35, =0.0032) in LUAD patients. CRABP2 can promote the progression of LUAD by promoting the G2/M phase transition, inhibiting the apoptosis and participating in the regulation of immune microenvironment. The high expression of CRABP2 will inhibit the recruitment of immune effector cells and promote the proportion of immuno-suppressive cells, thus promoting the progression of LUAD. The low expression of CRABP2 may enhance the expression of CD274(PD-L1), HAVCR2 and PDCD1LG2(PD-L2) in LUAD. While, the high expression of CRABP2 may enhance the expression of CTLA4, LAG3, PDCD1(PD-1), TIGIT and IGSF8 in LUAD. CRABP2 may be a valuable biomarker for diagnosis, treatment and prognosis of LUAD. Patients with high expression of CRABP2 in LUAD may have suboptimal efficacy when treated with inhibitors targeting CD274, HAVCR2, and PDCD1LG2, whereas they may experience better efficacy with inhibitors targeting CTLA4, LAG3, PDCD1, TIGIT, and IGSF8. Most of cancer patients with high CRABP2 expression may benefit from immune checkpoint inhibitor therapy. Our study results have laid a positive foundation for LUAD diagnosis and therapy.

References

Zhang B, Wang Y, Zhou X, Zhang Z, Ju H, Diao X . Construction of a Prognostic and Early Diagnosis Model for LUAD Based on Necroptosis Gene Signature and Exploration of Immunotherapy Potential. Cancers (Basel). 2022; 14(20). PMC: 9600876. DOI: 10.3390/cancers14205153. View

Gyorffy B, Surowiak P, Budczies J, Lanczky A . Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 2013; 8(12):e82241. PMC: 3867325. DOI: 10.1371/journal.pone.0082241. View

Mei J, Cai Y, Chen L, Wu Y, Liu J, Qian Z . The heterogeneity of tumour immune microenvironment revealing the CRABP2/CD69 signature discriminates distinct clinical outcomes in breast cancer. Br J Cancer. 2023; 129(10):1645-1657. PMC: 10646008. DOI: 10.1038/s41416-023-02432-6. View

Yin X, Chen S, Eisenbarth S . Dendritic Cell Regulation of T Helper Cells. Annu Rev Immunol. 2021; 39:759-790. DOI: 10.1146/annurev-immunol-101819-025146. View

Xiang C, Ji C, Cai Y, Teng H, Wang Y, Zhao R . Distinct mutational features across preinvasive and invasive subtypes identified through comprehensive profiling of surgically resected lung adenocarcinoma. Mod Pathol. 2022; 35(9):1181-1192. PMC: 9424111. DOI: 10.1038/s41379-022-01076-w. View

Lin H, Zhang X, Feng Y, Gong Z, Li J, Wang W . Advancing lung adenocarcinoma prognosis and immunotherapy prediction with a multi-omics consensus machine learning approach. J Cell Mol Med. 2024; 28(13):e18520. PMC: 11221067. DOI: 10.1111/jcmm.18520. View

Leon L, Gautier M, Allan R, Ilie M, Nottet N, Pons N . The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. Oncogene. 2019; 38(46):7146-7165. DOI: 10.1038/s41388-019-0935-y. View

Chen Q, Tan L, Jin Z, Liu Y, Zhang Z . Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro. Biomed Res Int. 2020; 2020:3098327. PMC: 7334762. DOI: 10.1155/2020/3098327. View

Liu C, Hsu Y, Kuo C, Jhuang J, Li Y, Cheng S . CRABP2 Is Associated With Thyroid Cancer Recurrence and Promotes Invasion via the Integrin/FAK/AKT Pathway. Endocrinology. 2022; 163(12). DOI: 10.1210/endocr/bqac171. View

10.

Sun N, Luo Y, Zheng B, Zhang Z, Zhang C, Zhang Z . A novel immune checkpoints-based signature to predict prognosis and response to immunotherapy in lung adenocarcinoma. J Transl Med. 2022; 20(1):332. PMC: 9310422. DOI: 10.1186/s12967-022-03520-6. View

11.

Paz-Ares L, Ciuleanu T, Cobo M, Schenker M, Zurawski B, Menezes J . First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(2):198-211. DOI: 10.1016/S1470-2045(20)30641-0. View

12.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

13.

Wang H, Zhang C, Peng K, Chen Z, Su J, Li Y . Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study. Cell Rep Med. 2023; 4(2):100911. PMC: 9975107. DOI: 10.1016/j.xcrm.2022.100911. View

14.

Jin B, Fu G, Jiang X, Pan H, Zhou D, Wei X . CRABP2 and FABP5 identified by 2D DIGE profiling are upregulated in human bladder cancer. Chin Med J (Engl). 2013; 126(19):3787-9. View

15.

Xie T, Tan M, Gao Y, Yang H . CRABP2 accelerates epithelial mesenchymal transition in serous ovarian cancer cells by promoting TRIM16 methylation via upregulating EZH2 expression. Environ Toxicol. 2022; 37(8):1957-1967. DOI: 10.1002/tox.23542. View

16.

Wu Y, Dziadziuszko R, Ahn J, Barlesi F, Nishio M, Lee D . Alectinib in Resected -Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024; 390(14):1265-1276. DOI: 10.1056/NEJMoa2310532. View

17.

Egan D, Moran B, Wilkinson M, Pinyol M, Guerra E, Gatius S . CRABP2 - A novel biomarker for high-risk endometrial cancer. Gynecol Oncol. 2022; 167(2):314-322. DOI: 10.1016/j.ygyno.2022.09.020. View

18.

Weber M, Schumacher S, Hannig W, Barth J, Lotzin A, Schafer I . Long-term outcomes of psychological treatment for posttraumatic stress disorder: a systematic review and meta-analysis. Psychol Med. 2021; 51(9):1420-1430. PMC: 8311818. DOI: 10.1017/S003329172100163X. View

19.

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379(21):2040-2051. DOI: 10.1056/NEJMoa1810865. View

20.

Robert C . A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020; 11(1):3801. PMC: 7393098. DOI: 10.1038/s41467-020-17670-y. View