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Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model 以 PAK1 为靶点可有效对抗合成小鼠模型中的皮肤鳞状细胞癌。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-19 DOI: 10.1111/cas.16246
Kazuhiro Okumura, Takao Morinaga, Megumi Saito, Yurika Tokunaga, Keisuke Otoyama, Sora Tanaka, Eriko Isogai, Masahito Kawazu, Yosuke Togashi, Yoshinori Hasegawa, Yuichi Wakabayashi
{"title":"Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model","authors":"Kazuhiro Okumura,&nbsp;Takao Morinaga,&nbsp;Megumi Saito,&nbsp;Yurika Tokunaga,&nbsp;Keisuke Otoyama,&nbsp;Sora Tanaka,&nbsp;Eriko Isogai,&nbsp;Masahito Kawazu,&nbsp;Yosuke Togashi,&nbsp;Yoshinori Hasegawa,&nbsp;Yuichi Wakabayashi","doi":"10.1111/cas.16246","DOIUrl":"10.1111/cas.16246","url":null,"abstract":"<p>By taking advantage of forward genetic analysis in mice, we have demonstrated that <i>Pak1</i> plays a crucial role during DMBA/TPA skin carcinogenesis. Although <i>Pak1</i> has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of <i>Pak1</i> in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer 不常见的表皮生长因子受体突变非小细胞肺癌的异质性肿瘤免疫微环境。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16253
Chong Zhang, Liangwei Yang, Weidi Zhao, Huangkai Zhu, Shuo Shi, Songan Chen, Guoqiang Wang, Bing Li, Guofang Zhao
{"title":"A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer","authors":"Chong Zhang,&nbsp;Liangwei Yang,&nbsp;Weidi Zhao,&nbsp;Huangkai Zhu,&nbsp;Shuo Shi,&nbsp;Songan Chen,&nbsp;Guoqiang Wang,&nbsp;Bing Li,&nbsp;Guofang Zhao","doi":"10.1111/cas.16253","DOIUrl":"10.1111/cas.16253","url":null,"abstract":"<p>Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1<sup>+</sup> cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (<i>p</i> &lt; 0.001), oxidative phosphorylation (<i>p</i> = 0.009), and transforming growth factor beta signaling (<i>p</i> = 0.01) pathways as well as increased expression of CTLA4 (<i>p</i> = 0.001) and PDCD1 (<i>p</i> = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon <i>EGFR</i> mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Zingiber officinale promotes autophagy and apoptosis in human oral cancer through the C/EBP homologous protein 人参通过C/EBP同源蛋白促进人类口腔癌的自噬和凋亡
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16248
Hyun-Ji Kim, Ji-Ae Shin, Yeong-Geun Lee, Bohwan Jin, Won Woo Lee, Yosub Lee, Su-Jung Choi, Jung-Min Han, Min-Hye Ahn, Ji-Hoon Kim, Dong-Guk Park, Seong-Doo Hong, Se-Chan Kang, Sung-Dae Cho
{"title":"Zingiber officinale promotes autophagy and apoptosis in human oral cancer through the C/EBP homologous protein","authors":"Hyun-Ji Kim,&nbsp;Ji-Ae Shin,&nbsp;Yeong-Geun Lee,&nbsp;Bohwan Jin,&nbsp;Won Woo Lee,&nbsp;Yosub Lee,&nbsp;Su-Jung Choi,&nbsp;Jung-Min Han,&nbsp;Min-Hye Ahn,&nbsp;Ji-Hoon Kim,&nbsp;Dong-Guk Park,&nbsp;Seong-Doo Hong,&nbsp;Se-Chan Kang,&nbsp;Sung-Dae Cho","doi":"10.1111/cas.16248","DOIUrl":"10.1111/cas.16248","url":null,"abstract":"<p>The rhizome of <i>Zingiber officinale</i> (<i>Z. officinale</i>), commonly known as ginger, has been characterized as a potential drug candidate due to its antitumor effects. However, the chemotherapeutic effect of ginger on human oral cancer remains poorly understood. In this study, we examined the effects of an ethanol extract of <i>Z. officinale</i> rhizomes (ZOE) on oral cancer and identified the components responsible for its pharmacological activity. ZOE exerts its inhibitory activity in oral cancer by inducing both autophagy and apoptosis simultaneously. Mechanistically, ZOE-induced autophagy and apoptosis in oral cancer are attributed to the reactive oxygen species (ROS)-mediated endoplasmic reticulum stress response. Additionally, we identified two active components of ZOE, 1-dehydro-6-gingerdione and 8-shogaol, which were sufficient to stimulate autophagy initiation and apoptosis induction by enhancing CHOP expression. These results suggest that ZOE and its two active components induce ROS generation, upregulate CHOP, initiate autophagy and apoptosis, and hold promising therapeutics against human oral cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Methyltransferase like-14 suppresses growth and metastasis of non-small-cell lung cancer by decreasing LINC02747 甲基转移酶 like-14 通过降低 LINC02747 抑制非小细胞肺癌的生长和转移。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16254
Jiemin Wang, Shu Wang, Haopeng Yang, Ruixuan Wang, Kesong Shi, Yueshi Liu, Le Dou, Haiquan Yu
{"title":"Methyltransferase like-14 suppresses growth and metastasis of non-small-cell lung cancer by decreasing LINC02747","authors":"Jiemin Wang,&nbsp;Shu Wang,&nbsp;Haopeng Yang,&nbsp;Ruixuan Wang,&nbsp;Kesong Shi,&nbsp;Yueshi Liu,&nbsp;Le Dou,&nbsp;Haiquan Yu","doi":"10.1111/cas.16254","DOIUrl":"10.1111/cas.16254","url":null,"abstract":"<p>Multiple epigenetic regulatory mechanisms exert critical roles in tumor development, and understanding the interactions and impact of diverse epigenetic modifications on gene expression in cancer is crucial for the development of precision medicine. We found that methyltransferase-like 14 (METTL14) was significantly downregulated in non-small-cell lung cancer (NSCLC) tissues. Functional experiments demonstrated that overexpression of METTL14 inhibited the proliferation and migration of NSCLC cells both in vivo and in vitro, and the colorimetric m<sup>6</sup>A quantification assay also showed that knockdown of METTL14 notably reduced global m<sup>6</sup>A modification levels in NSCLC cells. By using the methylated-RNA immunoprecipitation-qPCR and dual-luciferase reporter assays, we verified that long noncoding RNA LINC02747 was a target of METTL14 and was regulated by METTL14-mediated m<sup>6</sup>A modification, and silencing LINC02747 inhibited the malignant progression of NSCLC by modulating the PI3K/Akt and CDK4/Cyclin D1 signaling pathway. Further studies revealed that overexpression of METTL14 promoted m<sup>6</sup>A methylation and accelerated the decay of LINC02747 mRNA via increased recognition of the “GAACU” binding site by YTHDC2. Additionally, histone demethylase lysine-specific histone demethylase 5B (KDM5B) mediated the demethylation of histone H3 lysine 4 tri-methylation (H3K4me3) in the METTL14 promoter region and repressed its transcription. In summary, KDM5B downregulated METTL14 expression at the transcriptional level in a H3K4me3-dependent manner, while METTL14 modulated LINC02747 expression via m<sup>6</sup>A modification. Our results demonstrate a synergy of multiple mechanisms in regulating the malignant phenotype of NSCLC, revealing the complex regulation involved in the occurrence and development of cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target 揭示 UPF3B 在肝细胞癌中的作用:潜在的治疗目标。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16240
Bowen Hou, Min Shu, Chenghao Liu, Yunfeng Du, Cuicui Xu, Huijiao Jiang, Jun Hou, Xueling Chen, Lianghai Wang, Xiangwei Wu
{"title":"Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target","authors":"Bowen Hou,&nbsp;Min Shu,&nbsp;Chenghao Liu,&nbsp;Yunfeng Du,&nbsp;Cuicui Xu,&nbsp;Huijiao Jiang,&nbsp;Jun Hou,&nbsp;Xueling Chen,&nbsp;Lianghai Wang,&nbsp;Xiangwei Wu","doi":"10.1111/cas.16240","DOIUrl":"10.1111/cas.16240","url":null,"abstract":"<p>RNA-binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to <i>PPP2R2C</i>, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma 用 BRAF 抑制剂、TLR 7 激动剂和 PD-1 抗体三联疗法根除 BRAF 突变黑色素瘤的肿瘤。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16251
Kenta Nakamura, Tomonori Yaguchi, Masashi Murata, Yosuke Ota, Asuka Mikoshiba, Yukiko Kiniwa, Ryuhei Okuyama, Yutaka Kawakami
{"title":"Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma","authors":"Kenta Nakamura,&nbsp;Tomonori Yaguchi,&nbsp;Masashi Murata,&nbsp;Yosuke Ota,&nbsp;Asuka Mikoshiba,&nbsp;Yukiko Kiniwa,&nbsp;Ryuhei Okuyama,&nbsp;Yutaka Kawakami","doi":"10.1111/cas.16251","DOIUrl":"10.1111/cas.16251","url":null,"abstract":"<p>Programmed death 1 (PD-1)/programmed death-ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti-PD-1 antibody that blocks the major adaptive immune-resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune-resistant mechanisms, such as cancer cell-derived immunosuppressive cytokines, and a Toll-like receptor 7 agonist that enhances innate immune responses that promote antitumor T-cell induction and functions. Using a xenogeneic nude mouse model implanted with human <i>BRAF</i>-mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T-cell-stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll-like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon-α/natural killer cell pathways and augmenting the T-cell-stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine <i>BRAF</i>-mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100-specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti-PD-1 antibody resulted in complete regression of SIY antigen-transduced <i>BRAF</i>-mutated melanoma in a CD8 T-cell-dependent manner. These findings indicate that a triple-combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor-specific T cells may be crucial for effective tumor eradication.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microbiota and metabolite alterations in pancreatic head and body/tail cancer patients 胰头癌和胰体癌/胰尾癌患者的微生物群和代谢物变化。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16238
Yiqing Zhu, Xiao Liang, Guoming Zhang, Feng Li, Jianwei Xu, Ruiguang Ma, Xinyu Chen, Miaomiao Ma, Yifan Wang, Changxu Chen, Haoyun Tang, Lixiang Li, Zhen Li
{"title":"Microbiota and metabolite alterations in pancreatic head and body/tail cancer patients","authors":"Yiqing Zhu,&nbsp;Xiao Liang,&nbsp;Guoming Zhang,&nbsp;Feng Li,&nbsp;Jianwei Xu,&nbsp;Ruiguang Ma,&nbsp;Xinyu Chen,&nbsp;Miaomiao Ma,&nbsp;Yifan Wang,&nbsp;Changxu Chen,&nbsp;Haoyun Tang,&nbsp;Lixiang Li,&nbsp;Zhen Li","doi":"10.1111/cas.16238","DOIUrl":"10.1111/cas.16238","url":null,"abstract":"<p>Pancreatic head cancer (PHC) and pancreatic body/tail cancer (PBTC) have distinct clinical and biological behaviors. The microbial and metabolic differences in PHC and PBTC have not been studied. The pancreatic microbiota and metabolome of 15 PHC and 8 PBTC tissues and their matched nontumor tissues were characterized using 16S rRNA amplicon sequencing and untargeted metabolomics. At the genus level, <i>Bradyrhizobium</i> was increased while <i>Corynebacterium</i> and <i>Ruminococcus</i> were decreased in the PHC tissues (Head T) compared with the matched nontumor tissues (Head N) significantly. <i>Shuttleworthia</i>, <i>Bacillus</i>, and <i>Bifidobacterium</i> were significantly decreased in the PBTC tissues (Body/Tail T) compared with the matched nontumor tissues (Body/Tail N). Significantly, <i>Ileibacterium</i> was increased whereas <i>Pseudoxanthomonas</i> was decreased in Head T and Body/Tail T, and <i>Lactobacillus</i> was increased in Head T but decreased in Body/Tail T. A total of 102 discriminative metabolites were identified between Head T and Head N, which were scattered through linoleic acid metabolism and purine metabolism pathways. However, there were only four discriminative metabolites between Body/Tail T and Body/Tail N, which were related to glycerophospholipid metabolism and autophagy pathways. The differential metabolites in PHC and PBTC were commonly enriched in alpha-linolenic acid metabolism and choline metabolism in cancer pathways. <i>Eubacterium</i> decreased in Head T was positively correlated with decreased linoleic acid while negatively correlated with increased arachidyl carnitine and stearoylcarnitine. <i>Bacillus</i> decreased in Body/Tail T was negatively correlated with increased L-carnitine. These microbiota and metabolites deserve further investigations to reveal their roles in the pathogenesis of PHC and PBTC, providing clues for future treatments.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance SYT4与SNAP25结合,促进外泌体分泌和前列腺癌恩杂鲁胺耐药性的产生。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-18 DOI: 10.1111/cas.16239
Budeng Huang, Xiyue Deng, Guochao Zhou, Keqiang Li, Yuankang Feng, Guoqing Xie, Ruoyang Liu, Liang Song, Zhenlin Huang, Zhankui Jia
{"title":"SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance","authors":"Budeng Huang,&nbsp;Xiyue Deng,&nbsp;Guochao Zhou,&nbsp;Keqiang Li,&nbsp;Yuankang Feng,&nbsp;Guoqing Xie,&nbsp;Ruoyang Liu,&nbsp;Liang Song,&nbsp;Zhenlin Huang,&nbsp;Zhankui Jia","doi":"10.1111/cas.16239","DOIUrl":"10.1111/cas.16239","url":null,"abstract":"<p>Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in advanced HBV-HCC 晚期 HBV-HCC 中 PD-1+CD8 和 ICOS+Treg 细胞失衡的预后和治疗潜力。
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-15 DOI: 10.1111/cas.16247
Fengna Yan, Bingbing Zhu, Ke Shi, Yi Zhang, Xuanwei Zeng, Qun Zhang, Zhiyun Yang, Xianbo Wang
{"title":"Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in advanced HBV-HCC","authors":"Fengna Yan,&nbsp;Bingbing Zhu,&nbsp;Ke Shi,&nbsp;Yi Zhang,&nbsp;Xuanwei Zeng,&nbsp;Qun Zhang,&nbsp;Zhiyun Yang,&nbsp;Xianbo Wang","doi":"10.1111/cas.16247","DOIUrl":"10.1111/cas.16247","url":null,"abstract":"<p>Over 50% of patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) are diagnosed at an advanced stage, which is characterized by immune imbalance between CD8+ T cells and regulatory T (Treg) cells that accelerates disease progression. However, there is no imbalance indicator to predict clinical outcomes. Here, we show that the proportion of CD8+ T cells decreases and Treg cells increases in advanced HBV-HCC patients. During this stage, CD8+ T cells and Treg cells expressed the coinhibitory molecule PD-1 and the costimulatory molecule ICOS, respectively. Additionally, the ratio between PD-1+CD8 and ICOS+Tregs showed significant changes. Patients were further divided into high- and low-ratio groups: PD-1+CD8 and ICOS+Tregs high- (PD-1/ICOS<sup>hi</sup>) and low-ratio (PD-1/ICOS<sup>lo</sup>) groups according to ratio median. Compared with PD-1/ICOS<sup>lo</sup> patients, the PD-1/ICOS<sup>hi</sup> group had better clinical prognosis and weaker CD8+ T cells exhaustion, and the T cell-killing and proliferation functions were more conservative. Surprisingly, the small sample analysis found that PD-1/ICOS<sup>hi</sup> patients exhibited a higher proportion of tissue-resident memory T (T<sub>RM</sub>) cells and had more stable killing capacity and lower apoptosis capacity than PD-1/ICOS<sup>lo</sup> advanced HBV-HCC patients treated with immune checkpoint inhibitors (ICIs). In conclusion, the ratio between PD-1+CD8 and ICOS+Tregs was associated with extreme immune imbalance and poor prognosis in advanced HBV-HCC. These findings provide significant clinical implications for the prognosis of advanced HBV-HCC and may serve as a theoretical basis for identifying new targets in immunotherapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Alternative magnetic field exposure suppresses tumor growth via metabolic reprogramming 替代磁场暴露通过代谢重编程抑制肿瘤生长
IF 4.5 2区 医学
Cancer Science Pub Date : 2024-06-15 DOI: 10.1111/cas.16243
Taisuke Akimoto, Md Rafikul Islam, Akane Nagasako, Kazuhito Kishi, Rina Nakakaji, Makoto Ohtake, Hisashi Hasumi, Takashi Yamaguchi, Shigeki Yamada, Tetsuya Yamamoto, Yoshihiro Ishikawa, Masanari Umemura
{"title":"Alternative magnetic field exposure suppresses tumor growth via metabolic reprogramming","authors":"Taisuke Akimoto,&nbsp;Md Rafikul Islam,&nbsp;Akane Nagasako,&nbsp;Kazuhito Kishi,&nbsp;Rina Nakakaji,&nbsp;Makoto Ohtake,&nbsp;Hisashi Hasumi,&nbsp;Takashi Yamaguchi,&nbsp;Shigeki Yamada,&nbsp;Tetsuya Yamamoto,&nbsp;Yoshihiro Ishikawa,&nbsp;Masanari Umemura","doi":"10.1111/cas.16243","DOIUrl":"10.1111/cas.16243","url":null,"abstract":"<p>Application of physical forces, ranging from ultrasound to electric fields, is recommended in various clinical practice guidelines, including those for treating cancers and bone fractures. However, the mechanistic details of such treatments are often inadequately understood, primarily due to the absence of comprehensive study models. In this study, we demonstrate that an alternating magnetic field (AMF) inherently possesses a direct anti-cancer effect by enhancing oxidative phosphorylation (OXPHOS) and thereby inducing metabolic reprogramming. We observed that the proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz. In contrast, this exposure did not affect normal human astrocytes (NHA). Additionally, in mouse models implanted with human GBM cells in the brain, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival. This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression. The anti-cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger. Along with these observations, there was a decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR). This suggests that AMF-induced metabolic reprogramming occurs in GBM cells but not in normal cells. Our results suggest that AMF exposure may offer a straightforward strategy to inhibit cancer cell growth by leveraging oxidative stress through metabolic reprogramming.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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