USP51/ZEB1/ACTA2 axis promotes mesenchymal phenotype in gastric cancer and is associated with low cohesion characteristics

Liu, Yuanjie; Zeng, Shuhong; Zhang, Wei; Li, Jie-Pin; Yin, Yuefeng; Zhuang, Yingping; Zhou, Jin-Yong; Liu, Shenlin; Zou, Xi

doi:10.1016/j.phrs.2022.106644

Cited by 13 publications

(8 citation statements)

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“…To verify the specific infiltration of IFIT1 + PDL1 + TANs in PCC samples, we analyzed the potential physical interactions between IFIT1 + TANs and PCC cells. As a well-known EMT transcription factor, the unique function of ZEB1 in PCC cells has been demonstrated [ 20 ]. Thus, we used ZEB1 to label potential PCC cells in ST analysis.…”

Section: Resultsmentioning

confidence: 99%

“…We found here that tumor cells educate neutrophils in PCC via CXCL signaling to promote their PDL1 expression. Our previous work demonstrated that the EMT transcription factor ZEB1 is highly expressed in PCC, helping the tumors to maintain mesenchymal characteristics [ 20 ]. On this basis, we demonstrated that local ZEB1 expression in tumor tissues promoted IFIT1 + TANs infiltration.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated the presence of a large number of myofibroblasts and abundant blood vessels in the PCC microenvironment [20]. Here we attempted to with the intervention of macrophages over-/under-expressing SPP1.…”

Section: Ifit1 + Tans Promote Stromal Cell Activationmentioning

confidence: 99%

“…We previously identified an EMT signaling axis [Ubiquitin Specific Peptidase 51 (USP51)-Zinc Finger E-Box Binding Homeobox 1 (ZEB1)-Actin Alpha 2 (ACTA2)] in PCC, reinforcing the link between PCC and the mesenchymal phenotype [ 20 ]. In this study, by integrating a GC patient cohort, public datasets, and in vitro and in vivo models, we found that neutrophil-expressed Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) promoted EMT in GC, particularly in PCC-GC, and promoted mesenchymal cell recruitment through multiple signals, which subsequently facilitated an exhausted phenotype of T cells and induced resistance to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

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IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC)

Liu,

Li,

Han

et al. 2024

J Transl Med

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The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ifit1 + Tans Promote Stromal Cell Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC)

Liu,

Li,

Han

et al. 2024

J Transl Med

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“…An analysis of hepatocellular carcinoma showed that USP36 was also closely associated with macrophage infiltration (Sun, Shen, et al, 2022). Overexpression of USP51 in poorly cohesive gastric cancer has also been found to be associated with the recruitment of M2‐like TAMs to promote tumors (Liu et al, 2023).…”

Section: Effect Of the Ups On Tamsmentioning

confidence: 99%

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Xiao,

Liu,

et al. 2024

Journal Cellular Physiology

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Tumor‐associated macrophages (TAMs) are key components of the tumor microenvironment, and their different polarization states play multiple roles in tumors by secreting cytokines, chemokines, and so on, which are closely related to tumor development. In addition, the enrichment of TAMs is often associated with poor prognosis of tumors. Thus, targeting TAMs is a potential tumor treatment strategy, in which therapeutic approaches such as reducing TAMs numbers, remodeling TAMs phenotypes, and altering their functions are being extensively investigated. Meanwhile, the ubiquitin–proteasome system (UPS), an important mechanism of protein hydrolysis in eukaryotic cells, participates in cellular processes by regulating the activity and stability of key proteins. Interestingly, UPS plays a dual role in the process of tumor development, and its role in TAMs deserve to be investigated in depth. This review builds on this foundation to further explore the multiple roles of UPS on TAMs and identifies a promising approach to treat tumors by targeting TAMs with UPS.

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Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer

Li,

Bai,

et al. 2024

Biomedicine & Pharmacotherapy

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USP51/ZEB1/ACTA2 axis promotes mesenchymal phenotype in gastric cancer and is associated with low cohesion characteristics

Cited by 13 publications

References 50 publications

IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC)

IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC)

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer

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