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TRIM44 regulates tumor immunity in gastric cancer through LOXL2-dependent extracellular matrix remodeling

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Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Gastric cancer is a gastrointestinal malignancy with high mortality and poor prognosis, and the molecular mechanism of gastric tumorigenesis remains unclear. TRIM44 has been reported to be involved in tumor development. However, the role of TRIM44 in tumor immunity is largely unknown.

Methods

We analyzed TRIM44 expression in clinical gastric cancer tissues and normal tissues by using western blot, quantitative real-time PCR and bioinformatics analyses. We further investigated the involvement of TRIM44 in tumor immunity in vivo and found that it was dependent on extracellular matrix remodeling. We detected the interaction between TRIM44 and LOXL2 by using immunofluorescence staining and coimmunoprecipitation assays. We observed that TRIM44 mediates the stability of LOXL2 by ubiquitination assays.

Results

TRIM44 expression is high and is correlated with T-cell infiltration in gastric cancer. TRIM44 inhibits gastric tumorigenicity by regulating T-cell-mediated antitumor immunity and modulating the protein level of LOXL2. Mechanistically, TRIM44 directly binds to LOXL2 and affects the stability of LOXL2 to change extracellular matrix remodeling and influence tumor immunity.

Conclusion

These findings demonstrate that TRIM44 regulates the stability of LOXL2 to remodel the tumor extracellular matrix to modulate tumor immunity in gastric cancer and that the TRIM44/LOXL2 complex is a promising biomarker for gastric cancer prognosis and might be a novel immunotherapy target.

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Data Availability

The detailed raw data generated or analyzed in the current study will be provided by the corresponding author upon reasonable request. The associated analysis methods were based on published articles that were cited in the references.

Abbreviations

TRIM44:

Tripartite motif containing 44

LOXL2:

Lysyl oxidase-like 2

ECM:

Extracellular matrix

GSEA:

Gene set enrichment analysis

IF:

Immunofluorescence

IHC:

Immunohistochemical

PCR:

Polymerase chain reaction

CCK8:

Cell Counting Kit-8

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

a-SMA:

a-Smooth muscle actin

UB:

Ubiquitin

IB:

Immunoblotting

WCL:

Whole-cell lysate

DAPI:

4’,6-Diamidino-2-phenylindole

IP:

Immunoprecipitation

CHX:

Cycloheximide.

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Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, 250012, JiNan, China

    Xin Zhang, Yali Chu, Fengjun Liu & Cheng Chen

  2. Department of General Surgery, Linyi People’s Hospital, 105 Plaza Street, Linyi County, China

    Xiusheng Wu

  3. Department of Blood quality Control, Yantai central blood station, 10 Haiyun Road, Yantai, China

    Ying Sun

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  1. Xin Zhang
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Contributions

ZX and CC designed the study. ZX, CYL and SY performed the experiments. WXS and LFJ supervised the study. CC, ZX, SY, WXS and LFJ analyzed and interpreted the data. ZX and LFJ performed the statistical analysis. ZX and CC wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Cheng Chen.

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Zhang, X., Wu, X., Sun, Y. et al. TRIM44 regulates tumor immunity in gastric cancer through LOXL2-dependent extracellular matrix remodeling. Cell Oncol. 46, 423–435 (2023). https://doi.org/10.1007/s13402-022-00759-5

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