ATP13A2 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

Huang, Jinlan; Xu, Siyi; Zhou, Yu; Zheng, Yu; Yang, Bin; Ou, Qishui

doi:10.1007/s11605-021-05099-7

Cited by 5 publications

(4 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, other members of the P5B-ATPase family have been linked to different cancers 6 21 . ATP13A2 has been implicated in melanoma, colon cancer, hepatocellular carcinoma, acute myeloid leukemia and non-small-cell lung cancer 39 40 41 42 43 . We also reported that high ATP13A4 expression explains the increased polyamine uptake in the breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A 21 .…”

Section: Discussionmentioning

confidence: 99%

The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

Azfar,

Gao,

Van den Haute

et al. 2024

Preprint

View full text Add to dashboard Cite

High-risk neuroblastomas, often associated withMYCNoncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor DFMO, currently in clinical trial, and that this mechanism limits the efficacy of the drug. While this finding resulted in the clinical development of polyamine transport inhibitors including AMXT 1501, presently under clinical investigation in combination with DFMO, the mechanisms and transporters involved in DFMO-induced polyamine uptake are unknown. Knockdown of ATP13A3, a member of the P5B-ATPase family, limited basal and DFMO-induced polyamine uptake, attenuatedMYCN-amplified and non-MYCN-amplified neuroblastoma cell growth and potentiated the inhibitory effects of DFMO. Overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. The association between high ATP13A3 expression and poorer survival in neuroblastoma further supports a role of this transporter in neuroblastoma progression. Thus, this study identified ATP13A3 as a critical regulator of basal and DFMO-induced polyamine uptake and a novel therapeutic target for neuroblastoma.Graphical Abstract

show abstract

Section: Discussionmentioning

confidence: 99%

The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

Azfar,

Gao,

Van den Haute

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…ATP13A2 is a lysosomal transporter protein whose insufficient expression disrupts mitochondrial function and induces toxicity and cell death ( 39 ). Additionally, ATP13A2 is significantly associated with HCC prognosis ( 40 ). RNF7 plays a positive regulatory role in the progression of multiple malignant tumors ( 41 ), and it is associated with the fibrotic progression of HCC ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of copper metabolism-related genes is associated with the tumor immune microenvironment and predicts the prognosis of hepatocellular carcinoma

Kong,

Liu,

Yang

et al. 2024

Transl Cancer Res

View full text Add to dashboard Cite

Background Copper metabolism dysfunction has been found to be associated with the progression of various malignant tumors. The aim of this study is to explore the prognostic value of copper metabolism-related genes (CMRGs) in hepatocellular carcinoma (HCC) and their impact on the immune microenvironment. Methods We identified differentially expressed CMRGs in cancer and adjacent samples of HCC from The Cancer Genome Atlas (TCGA). Consensus clustering was performed to distinguish subgroups, and TIMER and CIBERSORT were applied to analyze the tumor immune microenvironment (TIME). We used the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis to establish a prognostic risk model for CMRGs. Gene set enrichment analysis (GSEA) was performed to elucidate potential signaling mechanisms associated with the risk group, as well as to determine and compare the tumor mutation burden (TMB), immune cell infiltration levels, and immune checkpoint of the identified risk groups. Results Two subgroups with significantly different survival rates were identified, with a better prognosis associated with high immune scores, high abundance of immune-infiltrating cells, and a relatively higher immune status. A prognostic risk model based on five CMRGs was constructed, which showed significant prognostic value. When combined with clinical feature column charts, this model can predict the prognosis of patients with HCC. Functional enrichment analysis showed that the low-risk group was enriched in a large number of metabolic pathways, while the high and low-risk groups exhibited different TMB and differential expression of immune checkpoint genes. The established model was validated in an independent International Cancer Genome Consortium (ICGC) dataset. Conclusions The results indicate that the expression of CMRGs is associated with the prognosis of HCC and the tumor microenvironment, and can serve as a predictive indicator for evaluating the prognosis of HCC.

show abstract

“…Many cancer types rely on an increased PTS, but it is unlikely that ATP13A4 is the only P5B-ATPase that is implicated in cancer. Indeed, ATP13A2 has been implicated in several human cancers, including melanoma [ 37 ], colon cancer [ 38 ], hepatocellular carcinoma [ 39 ], acute myeloid leukemia [ 40 ] and non-small-cell lung cancer [ 41 ], while ATP13A3 has been linked to pancreatic cancer and colorectal cancer [ 42 , 43 , 44 ]. Interestingly, high expression of ATP13A3 was found in metastatic pancreatic cancer cells with high polyamine uptake compared to slowly proliferating cells with low import activity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

et al. 2023

View full text Add to dashboard Cite

Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). Thus far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether the upregulation of candidate polyamine transporters of the P5B transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells presented elevated expression of a previously uncharacterized P5B-ATPase, ATP13A4, which was responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells were more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, the overexpression of ATP13A4 WT in MCF10A cells induced a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labeled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we established ATP13A4 as a new polyamine transporter in the human PTS and showed that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.

show abstract

ATP13A2 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

Cited by 5 publications

References 32 publications

The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

Expression of copper metabolism-related genes is associated with the tumor immune microenvironment and predicts the prognosis of hepatocellular carcinoma

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

Contact Info

Product

Resources

About