Journal of Extracellular Vesicles
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2023
·Vol. 12
·期 2
·e12310
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IF 16
Xiaoning Wang,Ruoyi Wu,Peisong Zhai,Zheqi Liu,Ronghui Xia,Zhen Zhang,Xing Qin,Chuwen Li,Wantao Chen,Jiang Li,Jianjun Zhang
Tumour cells under hypoxia tend to modulate the number and contents of extracellular vesicles (EVs) to regulate the tumour microenvironment (TME) and thus promote tumour progression. However, the mechanism of how hypoxia influences the secretion of EVs remains to be elucidated. Here, we confirm the increased production of EVs in head and neck squamous cell carcinoma (HNSCC) cells under hypoxia, where endosome-derived EVs are the main subtype affected by insufficient O 2 . The accumulation of hypoxia-inducible factor-1α (HIF-1α) under hypoxia directly downregulates the expression of ATP6V1A, which is pivotal to maintain the homeostasis of lysosomes. Subsequently, impaired lysosomal degradation contributes to the reduced fusion of multivesicular bodies (MVBs) with lysosomes and enables the secretion of intraluminal vesicles (ILVs) as EVs. These findings establish a HIF-1α-regulated lysosomal dysfunction-EV release axis and provide an exquisite framework to better understand EV biogenesis.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Changyun Yu,Chen Zhang,Qianqian Zhang,Cai Zhang,Jingjie Han,Jinying Li
Tripartite motif-containing 47 (TRIM47) is a member of the TRIM family, which has E3 ligase activity and has been demonstrated to be involved in tumor development. In this work, we found that TRIM47 is highly expressed in head and neck squamous cell carcinomas (HNSCC) tissues. TRIM47 overexpression promoted HNSCC cell proliferation. Downregulation of TRIM47 suppressed HNSCC cell proliferation and promoted apoptosis and autophagy. TRIM47 suppression caused cell proliferation inhibition and apoptosis promotion could be reversed by 3-MA, an autophagy inhibitor. In mechanism, TRIM47 interacted with XIAP-associated factor 1 (XAF1), promoting its ubiquitination and degradation. XAF1 promoted HNSCC cell apoptosis and autophagy. TRIM47 overexpression caused cell proliferation promotion and autophagy inhibition could be reversed by XAF1 overexpression. Animal experiments confirmed that the knockdown of TRIM47 inhibits tumor growth in vivo . Ultimately, TRIM47 promotes the ubiquitination and degradation of XAF1 and suppresses apoptosis and autophagy to promote the progression of HNSCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2026
·
IF 5.3
Fenqian Yuan,Jingkang Yong,Xueming Liu,Yifeng Wang,Dan Zhao
Background Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which epithelial–mesenchymal transition (EMT) contributes to tumor progression. Piezo1 and Galectin-1 have each been implicated in cancer progression, but their functional relationship in HNSCC remains incompletely understood. We investigated Piezo1-associated mechanosensitive signaling and its potential relationship with Galectin-1 in HNSCC. Methods Public transcriptomic and proteomic analyses were integrated with validation using 16 paired oral squamous cell carcinoma (OSCC) tumor and adjacent non-tumor specimens. Functional studies were performed in HNSCC cell lines using genetic and pharmacological modulation of PIEZO1/Piezo1 and Galectin-1-associated signaling. Two independent SCC-9 xenograft studies were conducted in separate cohorts (n = 6 per group): one comparing vehicle, Yoda1, and GsMTx4, and the other comparing vehicle, GsMTx4, OTX008, and their combination. Results Piezo1 was consistently upregulated in HNSCC datasets, OSCC tissues, and HNSCC cell lines, whereas its association with survival was modest and not uniformly reproduced across analytical platforms. Piezo1 activation was associated with increased Ca 2+ -associated signaling, nuclear YAP1 accumulation, and EMT-related phenotypes, whereas PIEZO1 silencing and pharmacological inhibition of mechanosensitive channel activity attenuated these effects. Galectin-1 emerged as a Piezo1-responsive candidate effector associated with YAP1 signaling and EMT-related phenotypes. OTX008 treatment reduced proliferation, wound closure, invasion, and EMT-related marker changes. In xenografts, combined GsMTx4 and OTX008 treatment produced greater reductions in tumor growth, Ki67 positivity, endpoint CD31 fluorescence intensity, and EMT-associated marker changes than either monotherapy at the tested doses. Conclusion These findings support an important contribution of Piezo1-associated mechanosensitive signaling to EMT-related phenotypes and tumor progression in HNSCC and support Galectin-1 as a functionally relevant, Piezo1-responsive candidate effector associated with YAP1 signaling. The greater antitumor effects observed with combined GsMTx4 and OTX008 treatment support further investigation of co-targeting mechanosensitive channel activity and Galectin-1 in HNSCC.
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DOI
PubMed
高影响因子
Biomaterials Advances
·
2025
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IF 6
Chen Wang,Yin Li,Xiaoxue Shen,Shiwei Xiao,Huiying Du,Qianye Zhao,Ying Wang,Qiangtao Zhang,Shuxin Wen
Background Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) exhibit poor survival due to tumor microenvironment (TME) barriers and systemic toxicity of chemo-immunotherapy associated with chemo-immunotherapy. Methods An injectable thermoresponsive hydrogel was engineered by crosslinking D-α-tocopheryl polyethylene glycol succinate (TPGS) with Na₂CO₃ (15 % w/v TPGS: 9 % w/v Na₂CO₃). This platform co-encapsulated doxorubicin-loaded nanoparticles (DOX NP) synthesized via PEI-cis-aconitic acid conjugation and CpG-loaded adjuvant nanoparticles (CpG NP) prepared through genipin-mediated PEI crosslinking. The hydrogel exhibited rapid temperature-triggered gelation, shear-thinning injectability, and a macroporous architecture that enabled dual drug retention and immune cell infiltration. Results In vitro , the hydrogel provided the sustained release of DOX NP with pH-responsive acceleration in acidic TME. In vivo , localized delivery of Gel-DOX NP-CpG NP significantly suppressed tumor growth ( p < 0.05) and enhanced cytotoxic CD8 + T-cell infiltration in TME (3.1-fold) and spleens (2.4-fold). RNA sequencing revealed 88 immune-related differentially expressed genes, including downregulated immunosuppressors and enriched cytokine pathways. Conclusion This TPGS/Na₂CO₃ hydrogel platform coordinates chemotherapy-induced immunogenic cell death (DOX NP) with CpG-driven innate immunity, overcoming TME barriers to enhance localized and systemic anti-tumor responses in HNSCC.
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DOI
PubMed
高影响因子
International Journal of Oral Science
·
2024
·Vol. 16
·期 1
·1-13
·
IF 10.8
Li Shujin,Feng Tian,Liu Yuantong,Yang Qichao,Song An,Wang Shuo,Xie Jun,Zhang Junjie,Yuan Bifeng,Sun Zhijun
N 1 -methyladenosine (m 1 A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m 1 A modification levels. Analysis of m 1 A-associated genes identified TRMT61A as a key m 1 A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m 1 A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m 1 A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m 1 A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m 1 A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2023
·
IF 4.6
Miao Deng,Jiaxin Guo,Zihang Ling,Chi Zhang,Lihong He,Zhaona Fan,Bin Cheng,Juan Xia
Gene mutations play an important role in head and neck squamous cell carcinoma (HNSCC) by not only promoting the occurrence and progression of HNSCC but also affecting sensitivity to treatment and prognosis. KRAS is one of the most frequently mutated oncogenes, which has been reported to have a mutation rate from 1.7% to 12.7% and may lead to poor prognosis in HNSCC, but its role remains unclear. Here, we found that the KRAS mutation can promote HNSCC generation through synergism with 4-Nitroquinoline-1-Oxide(4NQO). Mechanistically, KRAS mutations can significantly upregulate Runx1 to promote oral epithelial cell proliferation and migration and inhibit apoptosis. Runx1 inhibitor Ro 5-3335 can effectively inhibit KRAS -mutated HNSCC progression both in vitro and in vivo. These findings suggest that the KRAS mutation plays an important role in HNSCC and that Runx1 may be a novel therapeutic target for KRAS -mutated HNSCC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2023
·Vol. 28
·期 1
·1-10
·
IF 4.2
Gu Shanshan,Lin Chen,Li Yanguo,Wei Zhengyu,cao Bing,Shen Zhisen,Deng Hongxia
Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
American Journal of Cancer Research
·
2024
·
IF 3.6
Haiyue Zhu,Yuxin Bao,Xuanqi Dou,Xiaofeng Zuo,Junhong Ye,Haiyu Ma,Youquan Bu,Yitao Wang,Jiang Zhu
Head and neck squamous cell carcinoma (HNSCC) is a significant cause of mortality, while the underlying mechanism remains unclear. Our studies have revealed that KIF2C plays a crucial role in tumor proliferation and metastasis in HNSCC. The results demonstrate that KIF2C is highly expressed at both the mRNA and protein levels and is closely associated with lymph node metastasis. The gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicate that the differentially expressed genes are enriched in processes or pathways related to cell adhesion and cell mitosis in HNSCC. Moreover, the established protein-protein interaction network identifies KIF2C as a potential hub gene in HNSCC. Knockdown of KIF2C has been demonstrated to significantly reduce cell migration and invasion ability, leading to cell cycle arrest, a high proportion of abnormal cell apoptosis, and cell chromosome division mismatches in the HNSCC cell line. Downstream genes such as PDGFA, EGFR, TP63, SNAI2, KRT5, and KRT14 were found to be down-regulated, and multiple critical pathways, including mTOR, ERK, and PI3K-AKT pathways, were inactivated as a result of KIF2C knockdown. These findings provide strong evidence for the crucial role of KIF2C in HNSCC and suggest that targeting KIF2C may be a promising therapeutic strategy for this disease. Knockdown of KIF2C has been shown to significantly inhibit tumor proliferation in nude mice, demonstrating the potential therapeutic role of KIF2C in HNSCC treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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