Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma

Li, Min; Tang, Yuxiao; Wang, Dongyao; Zhai, Xiaofeng; Shen, Hui; Chen, Zhong; Yao, Man; Jin, Aiguo; Zhou, Zheng‐Jun; Zhou, Shao-Lai; Fan, Jia; Ling, Changquan; Chen, Ling

doi:10.1016/j.ymthe.2021.09.012

Cited by 26 publications

(20 citation statements)

References 42 publications

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“…In line with others' reports, our previous study confirmed that iron content was decreased in human liver tumor tissues compared with adjacent nontumor tissues ( n = 29). [ 13 ] To further investigate the alterations of iron‐metabolic molecules in HCC, we first retrieved the RNA‐sequencing date of liver tumor in The Cancer Genome Atlas (TCGA) database. Iron‐related genes were classified as iron ion homeostasis, iron ion transport, regulation of iron ion transport, and response to iron ion, according to Gene Ontology functions (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, as recorded by TCGA, the down‐regulation of HAMP was correlated with poor prognosis, implying potential influences of iron deficiency on liver cancer progressions. [ 13 ] In addition, the HAMP‐FPN axis, the main regulators of iron homeostasis in vivo , was identified to influence tumor malignancy, progress and prognosis, which highlighted the importance of iron metabolism in tumor biology.…”

Section: Discussionmentioning

confidence: 99%

“…The liver tumor tissues and nontumor counterparts used in this study were identical to our previous report. [ 13 ] Written informed consent was received from participants before inclusion in the study. Research Ethics Committees of Changhai Hospital, Second Military Medical University, granted ethical approval for the use of human liver tumor samples.…”

Section: Methodsmentioning

confidence: 99%

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Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma

Wang

Yang

et al. 2022

Hepatol Commun

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It is interesting that high iron is an independent inducer or cofactor of hepatocellular carcinoma (HCC) while the amount of iron is decreased in the liver tumor tissues. Due to the previous findings that iron deficiency promoted HCC metastasis, it is of significance to identify the underlying mechanism of iron deficiency in HCC. The tumor iron content and expressions of iron-metabolic molecules were observed in the primary liver cancers of rats and mice. The molecules that changed independently of iron were identified by comparing the expression profiles in the human HCC tissues and iron-deprived HCC cells. The downstream effects of these molecules on regulating intracellular iron content were investigated in vitro and further validated in vivo. Both in primary liver cancers of rats and mice, we confirmed the decreased iron content in tumor tissues and the altered expressions of iron-metabolic molecules, including transferrin receptor 1 (TfR1), six-transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), SLC46A1, ferroportin, hepcidin, and ferritin. Among these, STEAP3, DMT1, and SLC46A1 were altered free of iron deficiency. However, only silence or overexpression of SLC46A1 controlled the intracellular iron content of HCC cells. The interventions of STEAP3 or DMT1 could not change the intracellular iron content.Lentivirus-mediated regain of SLC46A1 expression restored the iron content in orthotopically implanted tumors, with correspondingly changes in the ironmetabolic molecules as iron increasing. Conclusion: Taken together, these results suggest that the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues, which would be an effective target to manage iron homeostasis in HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma

Wang

Yang

et al. 2022

Hepatol Commun

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“…In an iron-deficient mouse model of HCC, overexpression of SPNS2 also increased HCC metastasis, which was reduced upon SPNS2 ablation. However, these effects were immune cell independent, even though depleting SPNS2 again increased NK cells and effector T cells in the lungs [141]. These local immunostimulatory effects of SPNS2 ablation, despite its overall immunosuppressive effect during immunization, warrant further investigation.…”

Section: S1p Export and Tumor Immunitymentioning

confidence: 95%

Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity

Olesch

Brüne

Weigert

2022

IJMS

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The sphingolipid sphingosine-1-phosphate (S1P) promotes tumor development through a variety of mechanisms including promoting proliferation, survival, and migration of cancer cells. Moreover, S1P emerged as an important regulator of tumor microenvironmental cell function by modulating, among other mechanisms, tumor angiogenesis. Therefore, S1P was proposed as a target for anti-tumor therapy. The clinical success of current cancer immunotherapy suggests that future anti-tumor therapy needs to consider its impact on the tumor-associated immune system. Hereby, S1P may have divergent effects. On the one hand, S1P gradients control leukocyte trafficking throughout the body, which is clinically exploited to suppress auto-immune reactions. On the other hand, S1P promotes pro-tumor activation of a diverse range of immune cells. In this review, we summarize the current literature describing the role of S1P in tumor-associated immunity, and we discuss strategies for how to target S1P for anti-tumor therapy without causing immune paralysis.

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“…For instance, tumor growth in hepatocytes can be inhibited by using the AAV to mediate the CRISPR/Cas9 machinery ( 12 ). Li et al identified a new therapeutic target for the treatment of iron-regulated liver cancer metastasis by using rAAV8 (a recombinant AAV serotype 8 vector) to target mouse hepatocytes and decrease the production of SPNS2 (a protein linked to tumor metastasis) ( 13 ). For the first time, researchers led by Madisen demonstrated a link between hepatocyte replication and liver damage in adult mice given the recombinant AAV (rAAV) gene and the development of hepatocellular carcinoma ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus vector-mediated gene therapy for the treatment of ovarian cancer: a literature review

Zhu¹,

Qin²,

Wei³

et al. 2022

Ann Transl Med

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Background and Objective: The adeno-associated virus (AAV) is a member of the Parvoviridae family and has emerged as one of the most popular and promising approaches for gene therapy due to its low toxicity, low immunogenicity, and excellent safety after optimization. Advances in gene therapy methods have allowed novel treatments such as using AAV to knock out or repair target genes. AAV-mediated gene therapy has been used in numerous tumor studies, including lymphatic metastasis of prostate cancer, liver cancer, and renal cell carcinoma in mice. Ovarian cancer is an extremely aggressive malignancy which is prone to recurrence, and AAV vector-based gene therapy may be a potential treatment strategy.Methods: Herein, we reviewed the current research to provide an update on the role of AAV-mediated gene therapy in tumor research, especially in ovarian cancer. To find recent developments in pertinent research, we examined the PubMed database.Key Content and Findings: AAV vectors may produce steady and effective gene expression without becoming harmful, making it a viable gene delivery technique. AAV-based gene therapy products have been widely used in preclinical research and some have achieved marketing approval.Conclusions: Due to its affinity for various organs, reliable integration, and long-lasting expression, certain AAV serotypes have been widely used in gene therapy. However, there are also some challenges.Extensive research on the role of AAV in disease and gene therapy has shown great potential. Herein, we examined the literature to better understand the function of the AAV in tumor research, particularly in ovarian cancer research.

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Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma

Cited by 26 publications

References 42 publications

Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma

Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma

Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity

Adeno-associated virus vector-mediated gene therapy for the treatment of ovarian cancer: a literature review

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