Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer

Tomasich, Erwin; Topakian, Thaïs; Heller, Gerwin; Udovica, Simon; Krainer, Michael; Marhold, Maximilian

doi:10.1016/j.trsl.2020.11.005

Cited by 7 publications

(3 citation statements)

References 38 publications

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“…It has been reported that VPS37A KO leads to changes in cell morphology, promoting a mesenchymal like phenotype in SKOV3 and MDA-MB-468 cells [ 16 ]. In agreement with this, we observed that also RPE-1 VPS37A KO cells were slightly larger and more elongated compared to control RPE-1 cells.…”

Section: Resultsmentioning

confidence: 99%

Removal of hypersignaling endosomes by simaphagy

Migliano,

Schultz,

Wenzel

et al. 2023

Autophagy

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Activated transmembrane receptors continue to signal following endocytosis and are only silenced upon ESCRT-mediated internalization of the receptors into intralumenal vesicles (ILVs) of the endosomes. Accordingly, endosomes with dysfunctional receptor internalization into ILVs can cause sustained receptor signaling which has been implicated in cancer progression. Here, we describe a surveillance mechanism that allows cells to detect and clear physically intact endosomes with aberrant receptor accumulation and elevated signaling. Proximity biotinylation and proteomics analyses of ESCRT-0 defective endosomes revealed a strong enrichment of the ubiquitin-binding macroautophagy/autophagy receptors SQSTM1 and NBR1, a phenotype that was confirmed in cell culture and fly tissue. Live cell microscopy demonstrated that loss of the ESCRT-0 subunit HGS/HRS or the ESCRT-I subunit VPS37 led to high levels of ubiquitinated and phosphorylated receptors on endosomes. This was accompanied by dynamic recruitment of NBR1 and SQSTM1 as well as proteins involved in autophagy initiation and autophagosome biogenesis. Light microscopy and electron tomography revealed that endosomes with intact limiting membrane, but aberrant receptor downregulation were engulfed by phagophores. Inhibition of autophagy caused increased intra- and intercellular signaling and directed cell migration. We conclude that dysfunctional endosomes are surveyed and cleared by an autophagic process, simaphagy, which serves as a failsafe mechanism in signal termination. Abbreviations: AKT: AKT serine/threonine kinase; APEX2: apurinic/apyrimidinic endodoexyribonuclease 2; ctrl: control; EEA1: early endosome antigen 1; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HGS/HRS: hepatocyte growth factor-regulated tyrosine kinase substrate; IF: immunofluorescence; ILV: intralumenal vesicle; KO: knockout; LIR: LC3-interacting region; LLOMe: L-leucyl-L-leucine methyl ester (hydrochloride); MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; NBR1: NBR1 autophagy cargo receptor; PAG10: Protein A-conjugated 10-nm gold; RB1CC1/FIP200: RB1 inducible coiled-coil 1; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TUB: Tubulin; UBA: ubiquitin-associated; ULK1: unc-51 like autophagy activating kinase 1; VCL: Vinculin; VPS37: VPS37 subunit of ESCRT-I; WB: western blot; WT: wild-type.

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Section: Resultsmentioning

confidence: 99%

Removal of hypersignaling endosomes by simaphagy

Migliano,

Schultz,

Wenzel

et al. 2023

Autophagy

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“…Recently, María Belén Palma and co-authors exploit CRISPR/Cas9 editing method to break the expression of HLA-G in renal cell carcinoma and choriocarcinoma cell lines, which suggests a promising way to enhance the elimination of malignant cells [101]. Erwin Tomasich and his co-workers take advantage of this gene-editing technology to knock out HCC-related protein 1 in ovarian and breast cancer cells, which cause to a significant rise of PD-L1 expression by transcriptional activation of STAT3 [102]. Similarly, several researchers make use of CRISPR/Cas9 system to delete Cyclin-dependent kinase 5 (Cdk5) of melanoma cells After knocking out Cdk5, the PD-L1 is significantly decreased, and it have an important impact on improving the stimulation of against tumor of T cells [103].…”

Section: Indirect Regulation Of Crispr/cas9 In Immune Checkpoints Of ...mentioning

confidence: 99%

Current application and future perspective of CRISPR/cas9 gene editing system mediated immune checkpoint for liver cancer treatment

Tong,

Hu,

et al. 2024

Nanotechnology

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Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What’s more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum it all up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.

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“…Human hepatocellular carcinoma-related protein 1 (HCRP-1), which is also known as vacuolar protein sorting-associated protein 37A, is a subunit of the endosomal sorting complexes required for the transport I protein family, which mediates the internalization process of membrane protein ubiquitination in cells ( 10 ). HCRP-1 regulates the cell cycle, proliferation, migration and apoptosis, and maintains the survival of precursor cells prior to cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

HCRP‑1 alleviates the malignant phenotype and angiogenesis of oral squamous cell carcinoma cells via the downregulation of the EGFR/STAT3 signaling pathway

Yang

2022

Oncol Lett

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It has previously been reported that human hepatocellular carcinoma-related protein 1 (HCRP-1), which is a tumor suppressor gene, and epidermal growth factor receptor (EGFR) are abnormally expressed in certain solid tumors. Therefore, in the present study, the expression patterns of HCRP-1 in oral squamous cell carcinoma (OSCC) are discussed. Moreover, the present study investigated whether HCRP-1 regulated EGFR expression levels and its downstream effectors to further determine the regulation of tumor cell behavior. Therefore, the expression levels of HCRP-1 in normal oral epithelial and OSCC cells were determined, and the effects of HCRP-1 overexpression on OSCC cell proliferation, migration and invasion were assessed. Moreover, the culture medium from the different groups of OSCC cells was separately supplemented into the human umbilical vein endothelial cell (HUVEC) cultures, and the migration and angiogenesis of the HUVECs were assessed. To determine the roles of EGFR/STAT3 in the regulation of HCRP-1, EGF and colivelin, a STAT3 agonist, were used to treat CAL-27 cells and their effects on the cells were assessed using the aforementioned functional experiments. The results demonstrated that HCRP-1 expression levels were downregulated in OSCC cells and that HCRP-1 overexpression could suppress OSCC cell proliferation, migration and invasion. Moreover, the culture medium from OSCC cells overexpressing HCRP-1 facilitated the migration and angiogenesis of HUVECs. Furthermore, HCRP-1 was demonstrated to function in cells by regulating the EGFR/STAT3 signaling pathway. In summary, the present study indicated that HCRP-1 alleviated the malignant phenotype and angiogenesis of OSCC cells via the downregulation of the EGFR/STAT3 signaling pathway.

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Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer

Cited by 7 publications

References 38 publications

Removal of hypersignaling endosomes by simaphagy

Removal of hypersignaling endosomes by simaphagy

Current application and future perspective of CRISPR/cas9 gene editing system mediated immune checkpoint for liver cancer treatment

HCRP‑1 alleviates the malignant phenotype and angiogenesis of oral squamous cell carcinoma cells via the downregulation of the EGFR/STAT3 signaling pathway

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