Skip to main content
Top
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Cytostatic Therapy | Research

Expression and prognostic value of APOBEC2 in gastric adenocarcinoma and its association with tumor-infiltrating immune cells

Authors: Lipan Wei, Xiuqian Wu, Lan Wang, Ling Chen, Xuejun Wu, Tiantian Song, Yuanyuan Wang, Wenjun Chang, Aizhen Guo, Yongdong Niu, Haihua Huang

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear.

Methods

The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed.

Results

APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P < 0.05). APOBEC2 expression status were associated with the infiltration of CD66b+ TANs, differentiation grade, TNM stage, histological type and gender (all P < 0.05) in STAD. Little or no APOBEC2 expression was detected in STAD and adjacent normal tissues by western blot. We failed to show that APOBEC2 was an independent risk factor for OS (Hazard Ratio 0.816, 95%CI 0.574–1.161, P = 0.259) or DFS (Hazard Ratio 0.821, 95%CI 0.578–1.166, P = 0.270) in STAD by multivariate Cox regression analysis, but APOBEC2 negative subgroup has a worse OS and DFS among patients with adjuvant chemotherapy.

Conclusions

APOBEC2 correlates with CD66b, differentiation grade, TNM stages, histological classification, and gender in STAD. APOBEC2 is not an independent prognostic factor for STAD, our results suggest that patients with positive APOBEC2 can benefit from postoperative chemotherapy, and combination of APOBEC2 and CD66b is helpful to further stratify patients into different groups with distinct prognoses.
Appendix
Available only for authorised users
Literature
1.
go back to reference Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRefPubMed Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRefPubMed
2.
go back to reference Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021;134(7):783–91.CrossRefPubMed Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021;134(7):783–91.CrossRefPubMed
3.
go back to reference Yang L, Kartsonaki C, Yao P, de Martel C, Plummer M, Chapman D, Guo Y, Clark S, Walters RG, Chen Y, et al. The relative and attributable risks of cardia and non-cardia gastric cancer associated with Helicobacter pylori Infection in China: a case-cohort study. Lancet Public Health. 2021;6(12):e888–96.CrossRefPubMedPubMedCentral Yang L, Kartsonaki C, Yao P, de Martel C, Plummer M, Chapman D, Guo Y, Clark S, Walters RG, Chen Y, et al. The relative and attributable risks of cardia and non-cardia gastric cancer associated with Helicobacter pylori Infection in China: a case-cohort study. Lancet Public Health. 2021;6(12):e888–96.CrossRefPubMedPubMedCentral
4.
go back to reference Xie J, Fu L, Jin L. Immunotherapy of gastric cancer: past, future perspective and challenges. Pathol Res Pract. 2021;218:153322.CrossRefPubMed Xie J, Fu L, Jin L. Immunotherapy of gastric cancer: past, future perspective and challenges. Pathol Res Pract. 2021;218:153322.CrossRefPubMed
5.
go back to reference Kwak Y, Seo AN, Lee HE, Lee HS. Tumor immune response and immunotherapy in gastric cancer. J Pathol Transl Med. 2020;54(1):20–33.CrossRefPubMed Kwak Y, Seo AN, Lee HE, Lee HS. Tumor immune response and immunotherapy in gastric cancer. J Pathol Transl Med. 2020;54(1):20–33.CrossRefPubMed
6.
go back to reference Pecori R, Di Giorgio S, Paulo Lorenzo J, Nina Papavasiliou F. Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination. Nat Rev Genet. 2022;23(8):505–18.CrossRefPubMedPubMedCentral Pecori R, Di Giorgio S, Paulo Lorenzo J, Nina Papavasiliou F. Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination. Nat Rev Genet. 2022;23(8):505–18.CrossRefPubMedPubMedCentral
7.
go back to reference Okuyama S, Marusawa H, Matsumoto T, Ueda Y, Matsumoto Y, Endo Y, Takai A, Chiba T. Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis. Int J Cancer. 2012;130(6):1294–301.CrossRefPubMed Okuyama S, Marusawa H, Matsumoto T, Ueda Y, Matsumoto Y, Endo Y, Takai A, Chiba T. Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis. Int J Cancer. 2012;130(6):1294–301.CrossRefPubMed
8.
go back to reference Cladel NM, Jiang P, Li JJ, Peng X, Cooper TK, Majerciak V, Balogh KK, Meyer TJ, Brendle SA, Budgeon LR, et al. Papillomavirus can be transmitted through the blood and produce Infections in blood recipients: evidence from two animal models. Emerg Microbes Infect. 2019;8(1):1108–21.CrossRefPubMedPubMedCentral Cladel NM, Jiang P, Li JJ, Peng X, Cooper TK, Majerciak V, Balogh KK, Meyer TJ, Brendle SA, Budgeon LR, et al. Papillomavirus can be transmitted through the blood and produce Infections in blood recipients: evidence from two animal models. Emerg Microbes Infect. 2019;8(1):1108–21.CrossRefPubMedPubMedCentral
9.
go back to reference Li A, Wu J, Zhai A, Qian J, Wang X, Qaria MA, Zhang Q, Li Y, Fang Y, Kao W, et al. HBV triggers APOBEC2 expression through miR–122 regulation and affects the proliferation of Liver cancer cells. Int J Oncol. 2019;55(5):1137–48.PubMed Li A, Wu J, Zhai A, Qian J, Wang X, Qaria MA, Zhang Q, Li Y, Fang Y, Kao W, et al. HBV triggers APOBEC2 expression through miR–122 regulation and affects the proliferation of Liver cancer cells. Int J Oncol. 2019;55(5):1137–48.PubMed
10.
go back to reference Kostic C. Isolation and characterization of sixteen novel p53 response genes. Oncogene. 2000;19(35):3978–87.CrossRefPubMed Kostic C. Isolation and characterization of sixteen novel p53 response genes. Oncogene. 2000;19(35):3978–87.CrossRefPubMed
11.
go back to reference Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56.CrossRefPubMed Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56.CrossRefPubMed
12.
go back to reference Shi R, Wang X, Wu Y, Xu B, Zhao T, Trapp C, Wang X, Unger K, Zhou C, Lu S, et al. APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for Bladder cancer patients: evidence from pan-cancer analysis and multiple databases. Theranostics. 2022;12(9):4181–99.CrossRefPubMedPubMedCentral Shi R, Wang X, Wu Y, Xu B, Zhao T, Trapp C, Wang X, Unger K, Zhou C, Lu S, et al. APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for Bladder cancer patients: evidence from pan-cancer analysis and multiple databases. Theranostics. 2022;12(9):4181–99.CrossRefPubMedPubMedCentral
13.
go back to reference Vile RG, Melcher A, Pandha H, Harrington KJ, Pulido JS. APOBEC and Cancer Viroimmunotherapy: thinking the unthinkable. Clin Cancer Res. 2021;27(12):3280–90.CrossRefPubMedPubMedCentral Vile RG, Melcher A, Pandha H, Harrington KJ, Pulido JS. APOBEC and Cancer Viroimmunotherapy: thinking the unthinkable. Clin Cancer Res. 2021;27(12):3280–90.CrossRefPubMedPubMedCentral
14.
go back to reference Cescon DW, Haibe-Kains B, Mak TW. APOBEC3B expression in Breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation. Proc Natl Acad Sci U S A. 2015;112(9):2841–6.CrossRefPubMedPubMedCentral Cescon DW, Haibe-Kains B, Mak TW. APOBEC3B expression in Breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation. Proc Natl Acad Sci U S A. 2015;112(9):2841–6.CrossRefPubMedPubMedCentral
15.
go back to reference Swanton C, McGranahan N, Starrett GJ, Harris RS. APOBEC enzymes: mutagenic fuel for Cancer Evolution and Heterogeneity. Cancer Discov. 2015;5(7):704–12.CrossRefPubMedPubMedCentral Swanton C, McGranahan N, Starrett GJ, Harris RS. APOBEC enzymes: mutagenic fuel for Cancer Evolution and Heterogeneity. Cancer Discov. 2015;5(7):704–12.CrossRefPubMedPubMedCentral
16.
go back to reference Dutta A, Bhagat S, Paul S, Katz JP, Sengupta D, Bhargava D. Neutrophils in Cancer and potential therapeutic strategies using neutrophil-derived exosomes. Vaccines (Basel). 2023;11(6):1028.CrossRefPubMed Dutta A, Bhagat S, Paul S, Katz JP, Sengupta D, Bhargava D. Neutrophils in Cancer and potential therapeutic strategies using neutrophil-derived exosomes. Vaccines (Basel). 2023;11(6):1028.CrossRefPubMed
17.
go back to reference Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMed Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMed
18.
go back to reference 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(W1):W98–W102.CrossRefPubMedPubMedCentral 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(W1):W98–W102.CrossRefPubMedPubMedCentral
19.
go back to reference Huang X, Pan Y, Ma J, Kang Z, Xu X, Zhu Y, Chen J, Zhang W, Chang W, Zhu J. Prognostic significance of the infiltration of CD163(+) macrophages combined with CD66b(+) neutrophils in gastric cancer. Cancer Med. 2018;7(5):1731–41.CrossRefPubMedPubMedCentral Huang X, Pan Y, Ma J, Kang Z, Xu X, Zhu Y, Chen J, Zhang W, Chang W, Zhu J. Prognostic significance of the infiltration of CD163(+) macrophages combined with CD66b(+) neutrophils in gastric cancer. Cancer Med. 2018;7(5):1731–41.CrossRefPubMedPubMedCentral
20.
go back to reference Liao W, Hong SH, Chan BH, Rudolph FB, Clark SC. APOBEC-2, a Cardiac- and skeletal muscle-specific. Biochem Biophys Res Commun. 1999;260(2):398–404.CrossRefPubMed Liao W, Hong SH, Chan BH, Rudolph FB, Clark SC. APOBEC-2, a Cardiac- and skeletal muscle-specific. Biochem Biophys Res Commun. 1999;260(2):398–404.CrossRefPubMed
21.
go back to reference Meshcheryakova A, Pietschmann P, Zimmermann P, Rogozin IB, Mechtcheriakova D. AID and APOBECs as multifaceted intrinsic virus-restricting factors: emerging concepts in the light of COVID-19. Front Immunol. 2021;12:690416.CrossRefPubMedPubMedCentral Meshcheryakova A, Pietschmann P, Zimmermann P, Rogozin IB, Mechtcheriakova D. AID and APOBECs as multifaceted intrinsic virus-restricting factors: emerging concepts in the light of COVID-19. Front Immunol. 2021;12:690416.CrossRefPubMedPubMedCentral
22.
go back to reference Iio K, Nagasawa Y, Iwatani H, Yamamoto R, Horii A, Okuzaki D, Furumatsu Y, Inohara H, Nojima H, Imai E, et al. Microarray analysis of tonsils in immunoglobulin A Nephropathy patients. Biochem Biophys Res Commun. 2010;393(4):565–70.CrossRefPubMed Iio K, Nagasawa Y, Iwatani H, Yamamoto R, Horii A, Okuzaki D, Furumatsu Y, Inohara H, Nojima H, Imai E, et al. Microarray analysis of tonsils in immunoglobulin A Nephropathy patients. Biochem Biophys Res Commun. 2010;393(4):565–70.CrossRefPubMed
23.
go back to reference Matsumoto T, Marusawa H, Endo Y, Ueda Y, Matsumoto Y, Chiba T. Expression of APOBEC2 is transcriptionally regulated by NF-kappaB in human hepatocytes. FEBS Lett. 2006;580(3):731–5.CrossRefPubMed Matsumoto T, Marusawa H, Endo Y, Ueda Y, Matsumoto Y, Chiba T. Expression of APOBEC2 is transcriptionally regulated by NF-kappaB in human hepatocytes. FEBS Lett. 2006;580(3):731–5.CrossRefPubMed
24.
go back to reference Bert S, Nadkarni S, Perretti M. Neutrophil-T cell crosstalk and the control of the host inflammatory response. Immunol Rev. 2023;314(1):36–49.CrossRefPubMed Bert S, Nadkarni S, Perretti M. Neutrophil-T cell crosstalk and the control of the host inflammatory response. Immunol Rev. 2023;314(1):36–49.CrossRefPubMed
25.
go back to reference Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–92.CrossRefPubMed Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–92.CrossRefPubMed
26.
go back to reference Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8(8):CD004064.PubMed Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8(8):CD004064.PubMed
27.
go back to reference Wang D, Wang N, Li X, Chen X, Shen B, Zhu D, Zhu L, Xu Y, Yu Y, Shu Y. Tumor mutation burden as a biomarker in resected gastric cancer via its association with immune infiltration and hypoxia. Gastric Cancer. 2021;24(4):823–34.CrossRefPubMed Wang D, Wang N, Li X, Chen X, Shen B, Zhu D, Zhu L, Xu Y, Yu Y, Shu Y. Tumor mutation burden as a biomarker in resected gastric cancer via its association with immune infiltration and hypoxia. Gastric Cancer. 2021;24(4):823–34.CrossRefPubMed
28.
go back to reference Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, et al. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008;100(6):388–98.CrossRefPubMed Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, et al. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008;100(6):388–98.CrossRefPubMed
29.
go back to reference Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, et al. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with Surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006;17(2):262–9.CrossRefPubMed Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, et al. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with Surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006;17(2):262–9.CrossRefPubMed
30.
go back to reference Liu C, Zhang M, Yan X, Ni Y, Gong Y, Wang C, Zhang X, Wan L, Yang H, Ge C, et al. Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression. Sci Adv. 2023;9(4):eadd8977.CrossRefPubMedPubMedCentral Liu C, Zhang M, Yan X, Ni Y, Gong Y, Wang C, Zhang X, Wan L, Yang H, Ge C, et al. Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression. Sci Adv. 2023;9(4):eadd8977.CrossRefPubMedPubMedCentral
31.
go back to reference Li X, Zhang M, Lei T, Zou W, Huang R, Wang F, Huang Q, Wang C, Liu C. Single-cell RNA-sequencing dissects cellular heterogeneity and identifies two tumor-suppressing immune cell subclusters in HPV-related cervical adenosquamous carcinoma. J Med Virol. 2022;94(12):6047–59.CrossRefPubMed Li X, Zhang M, Lei T, Zou W, Huang R, Wang F, Huang Q, Wang C, Liu C. Single-cell RNA-sequencing dissects cellular heterogeneity and identifies two tumor-suppressing immune cell subclusters in HPV-related cervical adenosquamous carcinoma. J Med Virol. 2022;94(12):6047–59.CrossRefPubMed
32.
go back to reference Liu C, Li X, Huang Q, Zhang M, Lei T, Wang F, Zou W, Huang R, Hu X, Wang C, et al. Single-cell RNA-sequencing reveals radiochemotherapy-induced innate immune activation and MHC-II upregulation in Cervical cancer. Signal Transduct Target Ther. 2023;8(1):44.CrossRefPubMedPubMedCentral Liu C, Li X, Huang Q, Zhang M, Lei T, Wang F, Zou W, Huang R, Hu X, Wang C, et al. Single-cell RNA-sequencing reveals radiochemotherapy-induced innate immune activation and MHC-II upregulation in Cervical cancer. Signal Transduct Target Ther. 2023;8(1):44.CrossRefPubMedPubMedCentral
Metadata
Title
Expression and prognostic value of APOBEC2 in gastric adenocarcinoma and its association with tumor-infiltrating immune cells
Authors
Lipan Wei
Xiuqian Wu
Lan Wang
Ling Chen
Xuejun Wu
Tiantian Song
Yuanyuan Wang
Wenjun Chang
Aizhen Guo
Yongdong Niu
Haihua Huang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11769-3

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine