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P4HA3 drives cervical cancer lymphatic metastasis by facilitating ACLY-mediated ferroptosis resistance

ABSTRACT: The lymph node is the most common site of distant metastasis of cervical cancer (CCa), which elicits dismal prognosis and limited efficiency for treatment. Identification of the factors contributing to CCa lymphatic metastasis is needed to develop effective prevention and treatment strategies. Here, we found upregulation of prolyl 4-hydroxylase subunit alpha 3 (P4HA3), an α-subunit of prolyl hydroxylase, in lymphatic metastatic lesions of cervical cancer, which is strongly associated with poor prognosis. In vitro and in vivo experiments showed that P4HA3 promoted CCa lymphatic metastasis by conferring ATP-citrate lyase (ACLY)-mediated ferroptosis resistance. Mechanistically, P4HA3 stabilizes ACLY protein by competitively inhibiting its interaction with the E3 ubiquitin ligase UBR4, which prevents UBR4-mediated proteasomal degradation of ACLY. ACLY-derived acetyl-CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of SLC7A11 gene, ultimately enhancing SLC7A11 transcription and ferroptosis resistance. Collectively, our study provides a mechanistic understanding of the interplay between ferroptosis resistance and lymph node metastasis, providing a possibility to combat lymph node metastasis in cervical cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304077 | GEO | 2026/06/18

REPOSITORIES: GEO

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P4HA3 drives cervical cancer lymphatic metastasis by facilitating ACLY-mediated ferroptosis resistance [HeLa, SiHa]

Project description:The lymph node is the most common site of distant metastasis of cervical cancer (CCa), which elicits dismal prognosis and limited efficiency for treatment. Identification of the factors contributing to CCa lymphatic metastasis is needed to develop effective prevention and treatment strategies. Here, we found upregulation of prolyl 4-hydroxylase subunit alpha 3 (P4HA3), an α-subunit of prolyl hydroxylase, in lymphatic metastatic lesions of cervical cancer, which is strongly associated with poor prognosis. In vitro and in vivo experiments showed that P4HA3 promoted CCa lymphatic metastasis by conferring ATP-citrate lyase (ACLY)-mediated ferroptosis resistance. Mechanistically, P4HA3 stabilizes ACLY protein by competitively inhibiting its interaction with the E3 ubiquitin ligase UBR4, which prevents UBR4-mediated proteasomal degradation of ACLY. ACLY-derived acetyl-CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of SLC7A11 gene, ultimately enhancing SLC7A11 transcription and ferroptosis resistance. Collectively, our study provides a mechanistic understanding of the interplay between ferroptosis resistance and lymph node metastasis, providing a possibility to combat lymph node metastasis in cervical cancer.

2026-06-18 | GSE308704 | GEO

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis by a NGFR-dependent mechanism

Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in establishing the lymph node pre-metastatic niche by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and are taken up by lymphatic endothelial cells reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. Analysis of involved factors demonstrated that the neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended mice survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support that NGFR is secreted in sEVs favoring lymph node pre-metastatic niche formation and lymph node metastasis in melanoma.

2021-07-16 | PXD024108 | Pride

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through a NGFR-dependent mechanism

Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in the establishment of lymph node pre-metastatic niches by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. We found that neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells, inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended the survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support the idea that NGFR secreted in sEVs favors lymph node pre-metastatic niche formation and lymph node metastasis in melanoma

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Gene expression in early stage cervical cancer

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Transcription profiling of human early stage cervical cancer tumours WITH AND WITHOUT lymph node metastasis, IN ORDER TO predict lymph node metastasis BEFORE treatment.

Project description:Gene expression profiling of early stage cervical cancer tumours with and without lymph node metastasis, in order to predict lymph node metastasis before treatment. Subsequently, comparing gene expression profiles between healthy cervical tissue and early stage cervical cancer tissue. Experiment Overall Design: All patients had clinical FIGO stage IB-IIA cervical cancer, the low-risk group (N) included 19 patients without unfavourable prognostic factors (positive lymph nodes, parametrial invasion, positive margins or a combination of unfavourable prognostic factors); the high risk group (P) consisted of 16 patients with lymph node metastasis, who were treated with adjuvant radiation therapy with or without chemotherapy. Healthy cervical tissue biopsies (H) were collected from 5 non-cervical carcinoma patients who underwent hysterectomy for benign reasons. RNA pooled from all tumour tissue samples was used as reference sample. Log-ratios of five technical replicates were used for normalization.

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2026-01-19 | PXD063898 | Pride

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The different miRNA expression between cervical cancer tissues with or without lymph-node metastasis.

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