Vps34 Inhibits Hepatocellular Carcinoma Invasion by Regulating Endosome-Lysosome Trafficking via Rab7-RILP and Rab11

Qi, Chenyang; Zou, Liping; Mao, Xing; Hu, Yuan; Shi, Jiaoyu; Zhang, Zhigang; Wu, Huijuan

doi:10.4143/crt.2020.578

Cited by 5 publications

(5 citation statements)

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“…In addition, inhibition of PIK3C3 reduced invasion and promoted the death of trametinib-resistant melanoma cells in an in vivo zebrafish xenograft of metastatic melanoma [112]. In contrast, PIK3C3 inhibits the invasion of HCC cells by regulating endosome-lysosome trafficking via the Rab7-RILP pathway [10]. Our study showed that inhibition of PIK3C3 by miR-338-5p suppresses autophagy and induces CRC cell EMT, migration, invasion, and metastasis [12] (Figure 3).…”

Section: Migration Invasion and Metastasismentioning

confidence: 73%

“…Published research on PIK3C3 expression in human cancer tissues is scarce. Both increased and decreased levels of PIK3C3 protein have been reported in HCC [10,106]. In a series of 31 pairs of normal and esophageal SCC tissues, PIK3C3 mRNA levels were significantly lower in esophageal SCC tissues [92].…”

Section: Expression Of Pik3c3 In Human Cancermentioning

confidence: 89%

“…The complex includes PIK3C3, PIK3R4, BECN1, and UV radiation resistance associated gene (UVRAG) proteins [8,9] (Figure 1). PIK3C3 plays a key role in many human cancers, including hepatocellular carcinoma (HCC) [10], lung cancer [11], colorectal cancer (CRC) [12], and breast cancer [13], but the underlying mechanisms involved in tumorigenesis remain elusive. Moreover, PIK3C3 has been suggested to play a role in nonneoplastic diseases, such as autoimmune diseases, Alzheimer's disease, fibroproliferative liver diseases, and muscular dystrophy [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

Chu

Wang

Chen

et al. 2021

IJMS

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Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases.

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Section: Migration Invasion and Metastasismentioning

confidence: 73%

Section: Expression Of Pik3c3 In Human Cancermentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

Chu

Wang

Chen

et al. 2021

IJMS

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“…The PI3K/AKT/mTOR signaling pathway is one of the most critical intracellular signaling pathways controlling basic cellular functions, including cell proliferation, survival, metabolism, and locomotion (Yu et al 2021 ; Corti et al 2019 ). Using RNA-seq data analysis, we uncovered the mechanism of action of RILP in osteosarcoma, at least in part, through its regulation of the PI3K/AKT/mTOR pathway, which in turn regulated the proliferation, migration, and invasion of osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

RILP inhibits tumor progression in osteosarcoma via Grb10-mediated inhibition of the PI3K/AKT/mTOR pathway

Wei,

Xia,

Zheng

et al. 2023

Mol Med

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Background Rab-interacting lysosomal protein (RILP) contains an alpha-helical coil with an unexplored biological function in osteosarcoma. This study investigated the expression of RILP in osteosarcoma cells and tissues to determine the effect of RILP on the biological behaviors of osteosarcoma cells and the underlying mechanism. Methods Tumor Immune Estimation Resource (TIMER) database, The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were used for bioinformatic analysis. Co-immunoprecipitation experiment was used to determine whether the two proteins were interacting. In functional tests, cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay, transwell invasion assay, Immunofluorescence (IF) assay and immunohistochemical (IHC) assay were performed. Results Overexpression of RILP significantly inhibited proliferation and impaired metastasis ability of osteosarcoma cells, while silencing of RILP showed the opposite trend. RNA-seq data analysis was applied in 143B cells and pathway enrichment analysis revealed that differentially expressed genes were mainly enriched in the PI3K/AKT pathway. We further verified that overexpression of RILP restrained the PI3K/AKT/mTOR signaling pathway and induced autophagy in osteosarcoma cells, while the opposite trend was observed when PI3K pathway activator 740Y-P was used. 3-Methyladenine (3-MA), a selective autophagy inhibitor, partially attenuated the inhibitory effect of RILP on the migration and invasion ability of osteosarcoma cells, suggesting the involvement of autophagy in epithelial–mesenchymal transition regulation in osteosarcoma cells. Growth factor receptor binding protein-10 (Grb10), an adaptor protein, was confirmed as a potential target of RILP to restrain the PI3K/AKT signaling pathway. We subcutaneously injected stably overexpressing 143B osteosarcoma cells into nude mice and observed that overexpression of RILP inhibited tumor growth by inhibiting the PI3K/AKT/mTOR pathway. Conclusion Our study revealed that the expression of RILP was associated with favorable prognosis of osteosarcoma and RILP inhibits proliferation, migration, and invasion and promotes autophagy in osteosarcoma cells via Grb10-mediated inhibition of the PI3K/AKT/mTOR signaling pathway. In the future, targeting RILP may be a potential strategy for osteosarcoma treatment.

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“… 14 Vps34 controls lysosomal transport to prevent the tumor cells invasion in HCC. 15 It has been noted that GNS561 alters lysosomal function to have anti-HCC effects. 16 Lysosomal TRPML1 controls tumor cell mitochondrial activity to encourage HCC growth.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Lysosome-Related Biomarkers for Predicting Drug Candidates in Hepatocellular Carcinoma: An Insilco Analysis

Xu¹,

Zhang²,

Zhang³

2023

JHC

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Background Lysosomes play an important role in enhancing tumorigenesis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, a detailed analysis of the role of lysosome-related genes could improve the poor prognosis of HCC patients. Methods Lysosome-associated genes were downloaded from the GO and Genome Enrichment Analysis (GSEA) databases. After analyzing lysosome-associated differentially expressed genes (DEGs) between the TCGA and GTEx cohorts, we used univariate Cox regression, LASSO-Cox regression, stepwise Cox regression, and multivariate Cox regression analyses to build a predictive risk model. The ICGC cohort was used as a test cohort for the prognostic signature’s validation. It was also assessed how significantly the signature affected the tumor microenvironment (TME) and sensitivity to immune checkpoint inhibitors. To investigate the expression of this signature in clinical samples, qRT-PCR and immunohistochemistry (IHC) were carried out in 50 normal tissues and 59 HCC tissues. Results A total of 894 lysosome-associated genes were obtained. After identifying 113 lysosome-associated DEGs, we constructed a five-gene prognostic signature (RRAGD, AP1M2, CRHBP, NCSTN, and SLCO4C1) that can be effectively applied to the prognostic classification of HCC patients in TCGA and ICGC cohorts. Additionally, we discovered that this signature can affect the proportion of macrophage infiltration in TME. We also evaluated several tumor-sensitive medicines that affect this signature. Finally, we discovered that HCC tissues had lower amounts of CRHBP compared to normal tissues by the qRT-PCR and IHC assay. Conclusion We developed and validated a predictive signature of five lysosome-related genes for HCC patients and verified the downregulation of CRHBP expression in clinical samples, which may provide fresh perspectives for customized immunotherapy.

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Vps34 Inhibits Hepatocellular Carcinoma Invasion by Regulating Endosome-Lysosome Trafficking via Rab7-RILP and Rab11

Cited by 5 publications

References 29 publications

The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

RILP inhibits tumor progression in osteosarcoma via Grb10-mediated inhibition of the PI3K/AKT/mTOR pathway

Prognostic Lysosome-Related Biomarkers for Predicting Drug Candidates in Hepatocellular Carcinoma: An Insilco Analysis

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