Shiga‐like toxin I exerts specific and potent anti‐tumour efficacy against gastric cancer cell proliferation when driven by tumour‐preferential Frizzled‐7 promoter

Xu, Hao; Peng, Lijun; Shen, Mengjiao; Xia, Yanyan; Li, Zhiyang; He, Nongyue

doi:10.1111/cpr.12607

Cited by 5 publications

(7 citation statements)

References 36 publications

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“…Gene mutation, 5,6 loss of tumor suppressor and abnormal regulation of cell proliferation signaling pathway are all related to the occurrence and development of gastric cancer. 7,8 Therefore, it is very important for the diagnosis and treatment of gastric cancer to find effective early warning molecules, improve the early diagnosis and find out the molecular mechanism of invasion and metastasis of gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway</p>

Ji¹,

Zhang²

2020

OTT

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Aim: To explore the role of RPL38 on proliferation and apoptosis of gastric cancer cells by regulating miR-374b-5p/VEGF signal pathway. Methods: qRT-PCR was used to measure the expression of RPL38. CCK8 assay, Matrigel invasion assay, and flow cytometry were used to detect the role of RPL38in MKN-45 cells. Western blot was used to measure the protein expression of VEGF, pERK , ERK, p-AKT, AKT in cells. Dual-luciferase assay was performed to verify the relationship between miR-374b-5p and RPL38, miR-374b-5p and VEGF. Results: In our research, we found that RPL38 was upregulation in gastric cancer, loss function of RPL38 could inhibit MKN-45 cell proliferation and invasion, accompany with increasing apoptosis. Then, we verified that RPL38 could interact with miR-374b-5p by performed luciferase assay, there was a negative correlation between RPL38 and miR-374b-5p. Furthermore, we observed that VEGF is a potential target of miR-374b-5p, miR-374b-5p negatively regulated the expression of VEGF, and effected ERK/AKT signal pathways. Next, we found that miR-374b-5p inhibitor or overexpression of VEGF could prevent the antitumor function of si-RPL38. Conclusion: Knockdown of RPL38 inhibits the proliferation and apoptosis of gastric cancer via miR-374b-5p/VEGF signal pathway.

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Section: Introductionmentioning

confidence: 99%

<p>RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway</p>

Ji¹,

Zhang²

2020

OTT

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“…Gb3 expression has been detected in surgically resected tissue samples of human gastric carcinoma (both intestinal and diffuse types), as well as in endothelial cells from blood vessels and many other gastric cancer cell lines ( Geyer et al, 2016 ; Xu et al, 2019 ). Recombinant Stx1 plasmid vectors have been used to treat gastric cancer in vitro and in nude mouse xenografts, an approach which reduces cancer cell proliferation and tumor growth ( Xu et al, 2019 ).…”

Section: Pathological Function Of Gb3mentioning

confidence: 99%

Role of Globotriaosylceramide in Physiology and Pathology

Celi

Goldstein

Rosato-Siri

et al. 2022

Front. Mol. Biosci.

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At first glance, the biological function of globoside (Gb) clusters appears to be that of glycosphingolipid (GSL) receptors for bacterial toxins that mediate host-pathogen interaction. Indeed, certain bacterial toxin families have been evolutionarily arranged so that they can enter eukaryotic cells through GSL receptors. A closer look reveals this molecular arrangement allocated on a variety of eukaryotic cell membranes, with its role revolving around physiological regulation and pathological processes. What makes Gb such a ubiquitous functional arrangement? Perhaps its peculiarity is underpinned by the molecular structure itself, the nature of Gb-bound ligands, or the intracellular trafficking unleashed by those ligands. Moreover, Gb biological conspicuousness may not lie on intrinsic properties or on its enzymatic synthesis/degradation pathways. The present review traverses these biological aspects, focusing mainly on globotriaosylceramide (Gb3), a GSL molecule present in cell membranes of distinct cell types, and proposes a wrap-up discussion with a phylogenetic view and the physiological and pathological functional alternatives.

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“…Gb 3 is upregulated in many human cancers [81,82]. These include breast [72,83], ovarian [84,85], Burkitt's lymphoma [63], hairy cell leukemia [86], megakaryoblastic leukemia [87], myeloma [88], post-transplant lymphoproliferative disease [89], renal [90], colorectal [65,91], gastric [70,92], testicular [90,93], prostate [90], pancreatic [94][95][96], sarcoma [97], glioma [71], astrocytoma [98,99] and meningioma [100].…”

Section: Gb 3 Is a Cancer Markermentioning

confidence: 99%

“…VT has been shown effective to prevent the growth of many Gb 3 expressing human tumour xenografts in mice [65,70,90,98,100,104]. In these models, targeting of the neovasculature, in addition to the tumour per se, was observed [98,100,101].…”

Section: Gb 3 Is a Cancer Markermentioning

confidence: 99%

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Therapeutic Uses of Bacterial Subunit Toxins

Lingwood

2021

Toxins

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The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin–receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.

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Shiga‐like toxin I exerts specific and potent anti‐tumour efficacy against gastric cancer cell proliferation when driven by tumour‐preferential Frizzled‐7 promoter

Cited by 5 publications

References 36 publications

<p>RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway</p>

<p>RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway</p>

Role of Globotriaosylceramide in Physiology and Pathology

Therapeutic Uses of Bacterial Subunit Toxins

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