Role of collagen type Ⅰ alpha 1 chain in immune cell infiltration for diffuse gastric cancer and its impact on long-term survival_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Yuxia , HOU Yansong , JIAO Zuoyi ,  YU Zeyuan

Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, P. R. China;

Corresponding author：

YU Zeyuan, Email: yuzy17@lzu.edu.cn

Keywords：

diffuse gastric cancer; collagen type Ⅰ alpha 1 chain; Immune cell infiltration

DOI：

10.7507/1007-9424.202411022

Video：

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Objective To investigate the interplay between immune cell infiltration and extracellular matrix (ECM) remodeling in diffuse gastric cancer (DGC), and to identify novel diagnostic biomarkers and therapeutic targets. Methods Transcriptomic data of DGC patients from The Cancer Genome Atlas (TCGA) were analyzed to screen potential regulatory factors associated with immune-related and ECM receptor-related pathways. Differential expression of the identified regulator was evaluated between tumor and adjacent tissues. Bioinformatic analyses assessed its correlations with immune cell infiltration, ECM dynamics, and prognosis. Clinical validation was performed using 90 paraffin-embedded DGC tissue samples (tumor and matched adjacent tissues) from our hospital (January 2017 to December 2019). Immunohistochemistry (IHC) was applied to examine protein expression, followed by analysis of its associations with immune infiltration, clinicopathological features, and survival. Additionally, quantitative real-time PCR was conducted on 10 paired fresh DGC samples (2024 cohort) to validate mRNA expression. The significance level was set at α=0.05. Results Collagen type I alpha 1 chain (COL1A1) was identified as a key regulator linked to both immune suppression and ECM receptor pathways. COL1A1 was significantly upregulated in DGC tumors versus adjacent tissues (P<0.001) and correlated with poor prognosis [HR(95%CI)=2.9(1.21, 7.30), P=0.017]. Its expression negatively correlated with CD8⁺ T-cell infiltration (CIBERSORT: r=−0.17, P < 0.001; xCELL: r=−0.32, P<0.001) but positively associated with M2 tumor-associated macrophages (TAMs) (CIBERSORT: r=0.32; xCELL: r=0.24; both P<0.001). Clinical validation confirmed elevated COL1A1 protein/mRNA levels in tumors (both P<0.001). High COL1A1 protein expression predicted worse overall survival (P<0.001) and served as an independent risk factor for postoperative survival (HR=6.607, P<0.001) COL1A1 positively correlated with CD163 (M2 TAM marker, r=0.76, P< 0.001) and inversely with CD8⁺ T cells (r=−0.84, P<0.001). Conclusion COL1A1 is a pivotal mediator of immune evasion and ECM dysregulation in DGC, significantly impacting long-term survival. Targeting COL1A1 may represent a promising therapeutic strategy for DGC.

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15.	Jiang X, Ma Y, Wang T, et al. Targeting UBE2T potentiates gemcitabine efficacy in pancreatic cancer by regulating pyrimidine metabolism and replication stress. Gastroenterology, 2023, 164(7): 1232-1247.
16.	王凯瑞, 刘冬, 杨光, 等. COL1A1在肺腺癌中的表达以及对肿瘤进程的影响. 临床肺科杂志, 2024, 29(10): 1543-1549.
17.	毛雪宝, 王秀虹, 邱彬, 等. circ_0010423通过吸附miR-423-5p和miR-3184-5p上调COL1A1对宫颈癌恶性生物学行为的影响. 现代肿瘤医学, 2024, 32(11): 2001-2009.
18.	刘锐, 褚伟伟, 余明军, 等. lncRNAOIP5-AS1通过海绵吸附miR-143-3p调控COL1A1促进胃癌发展. 浙江中西医结合杂志, 2022, 32(9): 805-810,815.
19.	Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet, 2014, 46(6): 583-587.
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21.	Abyaneh HS, Regenold M, McKee TD, et al. Towards extracellular matrix normalization for improved treatment of solid tumors. Theranostics, 2020, 10(4): 1960-1980.
22.	Maller O, Drain AP, Barrett AS, et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater, 2021, 20(4): 548-559.
23.	Wang C, Zeng Q, Gül ZM, et al. Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy. Cell, 2024, 187(11): 2690-2702.
24.	Deng C, Huo M, Chu H, et al. Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. Mol Cancer, 2024, 23(1): 49. doi: 10.1186/s12943-024-01966-4.
25.	Wang Y, Zhang J, Shi H, et al. M2 tumor-associated macrophages-derived exosomal MALAT1 promotes glycolysis and gastric cancer progression. Adv Sci (Weinh), 2024, 11(24): e2309298. doi: 10.1002/advs.202309298.
26.	Hong SM, Lee AY, Kim BJ, et al. NAMPT-driven M2 polarization of tumor-associated macrophages leads to an immunosuppressive microenvironment in colorectal cancer. Adv Sci (Weinh), 2024, 11(14): e2303177. doi: 10.1002/advs.202303177.
27.	李媛, 孙景芬, 张玲, 等. 肾癌中COL1A1的表达对临床预后的价值及其与免疫浸润的相关性分析. 中国卫生统计, 2022, 39(3): 442-445.

1. 郑荣寿, 陈茹, 韩冰峰, 等. 2022年中国恶性肿瘤流行情况分析. 中华肿瘤杂志, 2024, 46(3): 221-231.
2. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
3. 李茁钰, 刘凯, 张维汉, 等. 全球及中国胃癌的流行病学特点及趋势: 2018–2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(10): 1236-1245.
4. Monster JL, Kemp LJS, Gloerich M, et al. Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer, 2022, 1877(3): 188719. doi: 10.1016/j.bbcan.2022.188719.
5. Petrelli F, Berenato R, Turati L, et al. Prognostic value of diffuse versus intestinal histotype in patients with gastric cancer: A systematic review and meta-analysis. J Gastrointest Oncol, 2017, 8(1): 148-163.
6. 孙孟婷, 王斌. 弥漫型胃癌的治疗探索. 中国肿瘤临床, 2023, 50(6): 302-308.
7. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10389): 1655-1668.
8. Wang K, Li E, Busuttil RA, et al. A cohort study and meta-analysis of the evidence for consideration of Lauren subtype when prescribing adjuvant or palliative chemotherapy for gastric cancer. Ther Adv Med Oncol, 2020, 12: 1758835920930359. doi: 10.1177/1758835920930359.
9. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2023, 24(11): 1181-1195.
10. Boku N, Omori T, Shitara K, et al. Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial. Gastric Cancer, 2024, 27(6): 1287-1301.
11. Pernot S, Terme M, Radosevic-Robin N, et al. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance. Gastric Cancer, 2020, 23(1): 73-81.
12. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 2021, 600(7890): 727-730.
13. Hegewisch-Becker S, Mendez G, Chao J, et al. First-line nivolumab and relatlimab plus chemotherapy for gastric or gastroesophageal junction adenocarcinoma: The phase Ⅱ RELATIVITY-060 study. J Clin Oncol, 2024, 42(17): 2080-2093.
14. Shi W, Wang Y, Xu C, et al. Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer. Nat Commun, 2023, 14(1): 835. doi: 10.1038/s41467-023-35797-6.
15. Jiang X, Ma Y, Wang T, et al. Targeting UBE2T potentiates gemcitabine efficacy in pancreatic cancer by regulating pyrimidine metabolism and replication stress. Gastroenterology, 2023, 164(7): 1232-1247.
16. 王凯瑞, 刘冬, 杨光, 等. COL1A1在肺腺癌中的表达以及对肿瘤进程的影响. 临床肺科杂志, 2024, 29(10): 1543-1549.
17. 毛雪宝, 王秀虹, 邱彬, 等. circ_0010423通过吸附miR-423-5p和miR-3184-5p上调COL1A1对宫颈癌恶性生物学行为的影响. 现代肿瘤医学, 2024, 32(11): 2001-2009.
18. 刘锐, 褚伟伟, 余明军, 等. lncRNAOIP5-AS1通过海绵吸附miR-143-3p调控COL1A1促进胃癌发展. 浙江中西医结合杂志, 2022, 32(9): 805-810,815.
19. Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet, 2014, 46(6): 583-587.
20. Schwörer S, Pavlova NN, Cimino FV, et al. Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment. Nat Metab, 2021, 3(11): 1484-1499.
21. Abyaneh HS, Regenold M, McKee TD, et al. Towards extracellular matrix normalization for improved treatment of solid tumors. Theranostics, 2020, 10(4): 1960-1980.
22. Maller O, Drain AP, Barrett AS, et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater, 2021, 20(4): 548-559.
23. Wang C, Zeng Q, Gül ZM, et al. Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy. Cell, 2024, 187(11): 2690-2702.
24. Deng C, Huo M, Chu H, et al. Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. Mol Cancer, 2024, 23(1): 49. doi: 10.1186/s12943-024-01966-4.
25. Wang Y, Zhang J, Shi H, et al. M2 tumor-associated macrophages-derived exosomal MALAT1 promotes glycolysis and gastric cancer progression. Adv Sci (Weinh), 2024, 11(24): e2309298. doi: 10.1002/advs.202309298.
26. Hong SM, Lee AY, Kim BJ, et al. NAMPT-driven M2 polarization of tumor-associated macrophages leads to an immunosuppressive microenvironment in colorectal cancer. Adv Sci (Weinh), 2024, 11(14): e2303177. doi: 10.1002/advs.202303177.
27. 李媛, 孙景芬, 张玲, 等. 肾癌中COL1A1的表达对临床预后的价值及其与免疫浸润的相关性分析. 中国卫生统计, 2022, 39(3): 442-445.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Latest ArticlesRole of collagen type Ⅰ alpha 1 chain in immune cell infiltration for diffuse gastric cancer and its impact on long-term survival

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