Cancer Science最新文献_第4页

Heterogeneity in Osteosarcoma Revealed by scRNA Sequencing: CLU+ Endothelial Cells as Key Players in Tumor Progression scRNA测序揭示骨肉瘤的异质性：CLU+内皮细胞在肿瘤进展中起关键作用。

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-07 DOI: 10.1111/cas.70138

Zhehao Dai, Peng Xie, Xiangzhi Bai, Tang Liu, Xiaoning Guo, Lei Kuang, Ping Mu, Fangjin Lu

{"title":"Heterogeneity in Osteosarcoma Revealed by scRNA Sequencing: CLU+ Endothelial Cells as Key Players in Tumor Progression","authors":"Zhehao Dai, Peng Xie, Xiangzhi Bai, Tang Liu, Xiaoning Guo, Lei Kuang, Ping Mu, Fangjin Lu","doi":"10.1111/cas.70138","DOIUrl":"10.1111/cas.70138","url":null,"abstract":"Osteosarcoma is a common malignant bone tumor in children and adolescents, characterized by high heterogeneity and poor prognosis. The role of intratumoral heterogeneity (ITH) in osteosarcoma progression remains poorly understood. To explore this, we collected paired tumor tissue samples from the central region (CR) and peripheral region (PR) of six osteosarcoma patients and performed single-cell RNA sequencing. Our findings reveal significant microenvironmental differences between these regions. The CR harbors a higher proportion of tumor cells, while the PR contains a higher proportion of endothelial cells, particularly the CLU+ subcluster. Functionally, the CR hosts a higher proportion of immune-activated myeloid cells and tumor-infiltrating lymphocytes (TILs), whereas the tumor cells in the PR show increased activation of hypoxia-related pathways. In the PR, CLU+ endothelial cells (CLU+_ECs) promote tumor metastasis by interacting with tumor cells through various ligands, including collagen family members, via ITGB1. Furthermore, CLU+_ECs induce CD8+ T cell exhaustion via the Nectin2-TIGIT pathway, suppressing the anti-tumor immune response. Overall, our study highlights the substantial spatial heterogeneity in osteosarcoma and identifies CLU+_ECs in the peripheral region as promising therapeutic targets.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2568-2579"},"PeriodicalIF":4.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585379","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

ONO-4578 Plus Nivolumab in Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer ONO-4578联合尼武单抗治疗晚期或复发性胃癌或胃食管结癌

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-06 DOI: 10.1111/cas.70130

Akihito Kawazoe, Kensei Yamaguchi, Tetsuya Hamaguchi, Yukiya Narita, Shogen Boku, Takashi Oshima, Hiroki Hara, Yasuo Hamamoto, Kenji Ishido, Taito Esaki, Hisashi Hosaka, Hirofumi Yasui, Keisuke Koeda, Tomohiro Nishina, Yasushi Tsuji, Takeo Fukagawa, Masahiro Goto, Eiji Oki, Naotoshi Sugimoto, Hiroshi Matsuoka, Fumiharu Yokoyama, Tomoko Yoshida, Kazuo Yoshida, Yoshiaki Oshima, Satoru Iwasa

{"title":"ONO-4578 Plus Nivolumab in Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer","authors":"Akihito Kawazoe, Kensei Yamaguchi, Tetsuya Hamaguchi, Yukiya Narita, Shogen Boku, Takashi Oshima, Hiroki Hara, Yasuo Hamamoto, Kenji Ishido, Taito Esaki, Hisashi Hosaka, Hirofumi Yasui, Keisuke Koeda, Tomohiro Nishina, Yasushi Tsuji, Takeo Fukagawa, Masahiro Goto, Eiji Oki, Naotoshi Sugimoto, Hiroshi Matsuoka, Fumiharu Yokoyama, Tomoko Yoshida, Kazuo Yoshida, Yoshiaki Oshima, Satoru Iwasa","doi":"10.1111/cas.70130","DOIUrl":"10.1111/cas.70130","url":null,"abstract":"ONO-4578, an EP4 antagonist, alone and combined with nivolumab, showed acceptable safety profiles and signs of antitumor activity in solid tumors. The expansion part examined the safety, preliminary efficacy, and biomarkers of ONO-4578 plus nivolumab in unresectable advanced or recurrent gastric or gastroesophageal junction (G/GEJ) cancer. Patients were enrolled into three groups: with previous immuno-oncology treatment (IO-treated; n = 30), without IO treatment (IO-naive; n = 30), and with UGT1A1 polymorphism (UGT1A1p; n = 6). Treatment-related adverse events (TRAEs) occurred in 46 patients (grade 3–4 in 17), with no grade 5 events reported. We confirmed the tolerability of the treatment in UGT1A1p. Objective response and disease control rates were 10.0% and 73.3%, respectively, in IO-treated and 16.7% and 40.0%, respectively, in IO-naive. Biomarker analysis indicated immune activation in the tumor microenvironment after the treatment. In conclusion, ONO-4578 plus nivolumab showed a manageable safety profile and antitumor activity in G/GEJ cancer.Trial Registration: Japan Registry of Clinical Trials number: jRCT2080223441; ClinicalTrials.gov identifier: NCT03155061","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2523-2536"},"PeriodicalIF":4.3,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576790","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

PRRX2 Regulates GLI2 to Promote Proliferation, Invasion, and Metastasis by Inhibiting Senescence via Hedgehog Signaling PRRX2通过抑制衰老信号调控GLI2促进增殖、侵袭和转移

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-06 DOI: 10.1111/cas.70134

Wei Huang, Feiqiang xu, Jichuan xu, Gang Quan, Shihang zhang, Mengmeng guo, Feng xiao, Jianxin jiang

{"title":"PRRX2 Regulates GLI2 to Promote Proliferation, Invasion, and Metastasis by Inhibiting Senescence via Hedgehog Signaling","authors":"Wei Huang, Feiqiang xu, Jichuan xu, Gang Quan, Shihang zhang, Mengmeng guo, Feng xiao, Jianxin jiang","doi":"10.1111/cas.70134","DOIUrl":"10.1111/cas.70134","url":null,"abstract":"Paired-related homeobox transcription factor 2 (PRRX2) belongs to the subfamily of homeobox genes and has been implicated as an oncogene in numerous cancer types, yet its role in pancreatic cancer requires further investigation. The aim of this study was to investigate the involvement of PRRX2 in pancreatic cancer progression. Bioinformatics analysis revealed that PRRX2, a transcription factor associated with senescence, was significantly upregulated in pancreatic cancer, and its heightened expression correlated with poor prognosis. Knockdown of PRRX2 led to an increased proportion of senescent cells and diminished proliferative, invasive, and metastatic capabilities, whereas PRRX2 overexpression yielded opposite effects. Subsequent experiments demonstrated that PRRX2 directly enhanced the transcription of GLI2, subsequently activating the hedgehog pathway, thereby inhibiting tumor senescence and promoting cell proliferation, invasion, and metastasis. Hedgehog pathway inhibitors or silencing of GLI2 partially reversed these effects. Additional replication experiments revealed that senescence inducers could partially counteract the impact of PRRX2 on pancreatic cancer. In conclusion, PRRX2 may serve as a potential therapeutic target for pancreatic cancer treatment.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2427-2443"},"PeriodicalIF":4.3,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576791","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

Survival Benefit of Surgical Staging Before Radiotherapy in Locally Advanced Cervical Cancer: A Pooled Analysis 局部晚期宫颈癌放疗前手术分期的生存获益：一项汇总分析。

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-06 DOI: 10.1111/cas.70136

Huazhong Xu, Qu Zhang, Chengyan Luo, Mei Wang, Meng Tian, Xinchen Sun, Qin Qin

{"title":"Survival Benefit of Surgical Staging Before Radiotherapy in Locally Advanced Cervical Cancer: A Pooled Analysis","authors":"Huazhong Xu, Qu Zhang, Chengyan Luo, Mei Wang, Meng Tian, Xinchen Sun, Qin Qin","doi":"10.1111/cas.70136","DOIUrl":"10.1111/cas.70136","url":null,"abstract":"Lymph node metastasis significantly impacts prognosis and treatment in locally advanced cervical cancer (LACC). Surgical staging offers precise information on node involvement, though its survival benefit is debated. We pooled data from 9 cohort studies involving 2553 patients to evaluate the benefit of pre-treatment surgical staging in patients with locally advanced cervical cancer. Fixed effects models or random effects models were used to calculate the pooled hazard ratios (HRs). The overall pooled results showed no difference in PFS (HR 0.94, 95% CI 0.73–1.22, p = 0.65) or OS (HR 1.00, 95% CI 0.74–1.35, p = 0.99) between the two approaches of lymph node staging. However, the subgroup analyses found the PFS superiority of surgical staging in patients with FIGO stage II (HR 0.68, 95% CI 0.49–0.95, p = 0.02). Additionally, for the patients with no evidence of lymph node metastasis on imaging, surgical staging was associated with significantly improved PFS (HR 0.69, 95% CI 0.56–0.86, p = 0.001) and OS (HR 0.56, 95% CI 0.36–0.87, p = 0.01). In the subgroup of patients with suspicious bulky nodes on imaging, lymph node debulking-based surgical staging did not significantly improve either PFS (HR 0.97, 95% CI 0.72–1.31, p = 0.31) or OS (HR 1.16, 95% CI 0.68–1.99, p = 0.59) in comparison with imaging staging. Surgical staging may not be applicable to all patients with LACC. However, for the patients with FIGO II disease or those without suspicious lymph node involvement on imaging, node surgery staging could afford a survival benefit.Trial Registration: PROSPERO ID: CRD42024543768","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2537-2546"},"PeriodicalIF":4.3,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576792","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

Correction to “Upregulation of HLA-II Related to LAG-3+CD4+ T Cell Infiltration is Associated With Patient Outcome in Human Glioblastoma” 更正“与LAG-3+CD4+ T细胞浸润相关的HLA-II上调与人胶质母细胞瘤患者预后相关”。

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-01 DOI: 10.1111/cas.70135

引用次数: 0

KLHL5 Contributes to Colorectal Cancer Cell Survival by Promoting Cell Cycle Progression and Suppressing Apoptotic Cell Death KLHL5通过促进细胞周期进程和抑制凋亡细胞死亡参与结直肠癌细胞存活。

IF 4.3 2区医学

Cancer Science Pub Date : 2025-07-01 DOI: 10.1111/cas.70108

Kyosuke Habu, Yosuke Matsuoka, Hiromi Hiyoshi, Jun Nakayama, Katsuya Watanabe, Sota Tate, Tomohisa Sakaue, Junko Murai, Konomu Uno, Hirotada Nishie, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Yuji Watanabe, Taro Oshikiri, Shigeki Higashiyama

{"title":"KLHL5 Contributes to Colorectal Cancer Cell Survival by Promoting Cell Cycle Progression and Suppressing Apoptotic Cell Death","authors":"Kyosuke Habu, Yosuke Matsuoka, Hiromi Hiyoshi, Jun Nakayama, Katsuya Watanabe, Sota Tate, Tomohisa Sakaue, Junko Murai, Konomu Uno, Hirotada Nishie, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Yuji Watanabe, Taro Oshikiri, Shigeki Higashiyama","doi":"10.1111/cas.70108","DOIUrl":"10.1111/cas.70108","url":null,"abstract":"Kelch-like protein 5 (KLHL5) is highly expressed in colorectal cancer (CRC) compared to that in adjacent normal mucosa, and its expression level increases with CRC stage, showing a correlation with poor prognostic factors. However, its functional role in the malignant progression still remains unknown. To elucidate the role of KLHL5 in CRC, we characterized human CRC cell lines, including HCT116 and SW480, under KLHL5-depleted conditions. KLHL5-depleted HCT116 and SW480 cells suppressed their growth and migration in culture. Further duration induced cell death characterized by apoptotic cell death with down-regulation of antiapoptotic factor Bcl-2 and up-regulation of proapoptotic factors Bac, Boc, Puma, Bid, Noxa, and Bik. Proteomic analyses indicated KLHL5 depletion suppressed cell cycle progression by affecting multiple pathways, including the activation of the G2/M DNA damage pathway and inhibition of the G1/S transition. Further biochemical and cell biological analyses revealed the downregulation of CDT1 and CDC6 proteins, which are essential factors for the initiation of DNA replication, and the downregulation of cyclins A and B, which are essential factors for the progression of S and G2/M phases. Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2444-2456"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545724","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 14-Gene Panel for Predicting Colorectal Cancer Recurrence Using Circulating Tumor DNA in Different Testing Conditions 使用循环肿瘤DNA在不同测试条件下预测结直肠癌复发的14个基因小组。

IF 4.3 2区医学

Cancer Science Pub Date : 2025-06-30 DOI: 10.1111/cas.70114

Yuichi Hisamatsu, Koji Ando, Kensuke Kudo, Ryota Nakanishi, Tetsuro Kawazoe, Yoko Zaitsu, Tetsuya Kusumoto, Taishi Hata, Yoshinori Kagawa, Tomoharu Yoshizumi, Naoko Ashida, Hayato Niiro, Takashi Hirose, Eiji Oki

{"title":"A 14-Gene Panel for Predicting Colorectal Cancer Recurrence Using Circulating Tumor DNA in Different Testing Conditions","authors":"Yuichi Hisamatsu, Koji Ando, Kensuke Kudo, Ryota Nakanishi, Tetsuro Kawazoe, Yoko Zaitsu, Tetsuya Kusumoto, Taishi Hata, Yoshinori Kagawa, Tomoharu Yoshizumi, Naoko Ashida, Hayato Niiro, Takashi Hirose, Eiji Oki","doi":"10.1111/cas.70114","DOIUrl":"10.1111/cas.70114","url":null,"abstract":"Detecting minimal residual disease after surgery is critical for assessing colorectal cancer recurrence risk. Traditional methods, including histology and carcinoembryonic antigen testing, have limited sensitivity. As circulating tumor DNA has emerged as a promising minimal residual disease biomarker, we evaluated circulating tumor DNA detection using a sensitive, targeted 14-gene panel, the Sysmex Plasma-Safe-SeqS colorectal cancer assay, in resectable colorectal cancer cases. We enrolled 46 Japanese patients with preoperatively diagnosed stage II colorectal cancer who underwent surgery at three institutions. Plasma samples were collected pre- and postoperatively. Tumor-informed, plasma-informed, and tumor-naive Plasma-Safe-SeqS colorectal cancer assays were performed. Patients were followed for a median of 1169 (range 148–1476) days using clinical assessments and computed tomography scans. Variants in tumor tissue were detected in 45 of 46 cases (98%). Preoperative circulating tumor DNA was detected in 32 (70%) and postoperative circulating tumor DNA in 16 (35%) patients. Postoperative circulating tumor DNA predicted recurrence with 33%, 38%, and 25% of positive percent agreement for tumor-informed, plasma-informed, and tumor-naive assays, respectively. The tumor-naive assay detected more postoperative circulating tumor DNA-positive cases than the others. As the tumor-naive approach does not require preoperative genetic profiling, it offers significant advantages in cost and ease of implementation in routine clinical practice. Further large-scale studies are warranted to optimize detection strategies.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2499-2506"},"PeriodicalIF":4.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530613","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

Epigenetically-Upregulated CD98 Shed Light on the Precancerous Diagnosis and Prognosis Prediction of Esophageal Cancer 表观遗传学上调CD98在食管癌癌前诊断和预后预测中的作用

IF 4.3 2区医学

Cancer Science Pub Date : 2025-06-30 DOI: 10.1111/cas.70128

Xue Zhang, Mengfei Sun, Na Li, Jie Yu, Wenjie Wang, Ju Yang, Hongyan Wu, Linyue Zhao, Huakun Zhang, Lan Yang, Feng Li, Qi Sun, Yunzhao Chen, Xiaobin Cui

{"title":"Epigenetically-Upregulated CD98 Shed Light on the Precancerous Diagnosis and Prognosis Prediction of Esophageal Cancer","authors":"Xue Zhang, Mengfei Sun, Na Li, Jie Yu, Wenjie Wang, Ju Yang, Hongyan Wu, Linyue Zhao, Huakun Zhang, Lan Yang, Feng Li, Qi Sun, Yunzhao Chen, Xiaobin Cui","doi":"10.1111/cas.70128","DOIUrl":"10.1111/cas.70128","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) has a significantly low survival rate, primarily due to the lack of diagnostic markers for early diagnosis and effective therapies. Recently, CD98 has been proposed as a specific marker of mature esophageal basal cells, which may be associated with esophageal carcinogenesis. Therefore, we aimed to investigate the clinical significance and biological function of CD98 in ESCC progression, as well as the value of CD98 as a potential new marker for the early diagnosis of ESCC. Through MassARRAY system spectroscopy, DIA proteomics analysis, immunohistochemical and functional experiments, we found hypomethylation-linked upregulation of CD98 expression, which was associated with poor prognosis, promoted cell proliferation by regulating the cell cycle in ESCC. Furthermore, we not only demonstrated that the range of CD98 expression was consistent with that of dysplastic cells in 73.81% of low-grade intraepithelial neoplasia (LGIN) and 83.08% of high-grade intraepithelial neoplasia (HGIN) cases, but also confirmed the expression level of CD98 was positively correlated with the classical diagnosis marker P53. Compared to using P53 alone, the combination of the immunohistochemical markers CD98 and P53 (either one was positive) provided more accurate diagnostic data for LGIN (92.86% vs. 88.10%, p < 0.01) and HGIN (93.85% vs. 73.85%, p < 0.01). In summary, we propose that CD98 is involved in a crucial step in ESCC carcinogenesis, and when combined with P53, may serve as a diagnostic marker for ESCC precancerous lesions.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2592-2606"},"PeriodicalIF":4.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70128","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530614","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

SHBs Mitigates Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma via Activation of RAF1/MEK/ERK Signaling Pathway SHBs通过激活RAF1/MEK/ERK信号通路减轻索拉非尼诱导的肝癌细胞凋亡

IF 4.3 2区医学

Cancer Science Pub Date : 2025-06-28 DOI: 10.1111/cas.70132

Shuxiang Wu, Yuxiang Hong, Hang Li, Mengxian Lin, Xiaohuang Lin, Xinjian Lin, Xu Lin

{"title":"SHBs Mitigates Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma via Activation of RAF1/MEK/ERK Signaling Pathway","authors":"Shuxiang Wu, Yuxiang Hong, Hang Li, Mengxian Lin, Xiaohuang Lin, Xinjian Lin, Xu Lin","doi":"10.1111/cas.70132","DOIUrl":"10.1111/cas.70132","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, with a significant association to hepatitis B virus (HBV) infection, which has been shown to drive HCC progression. Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced HCC. However, recent studies indicate that HBV infection may confer resistance to sorafenib treatment. The small hepatitis B surface antigen (SHBs), the most abundant HBV viral protein, has been implicated in HCC development, yet its role in sorafenib resistance is unclear. This study demonstrates that SHBs promotes sorafenib resistance in HCC cells and xenograft models by inhibiting apoptosis. Upon sorafenib treatment, SHBs expression was found to enhance the RAF1/MEK/ERK signaling pathway, as evidenced by increased phosphorylation of ERK and MEK. Inhibition of ERK activity with U0126 countered SHBs effects on sorafenib-induced apoptosis, cleaved caspase-3, and cellular proliferation. Mechanistically, SHBs binds to protein tyrosine phosphatase non-receptor type 1 (PTPN1), enhancing its phosphorylation, which subsequently dephosphorylates the protein tyrosine phosphatase interacting protein 51 (PTPIP51). This dephosphorylation promotes RAF1 recruitment to the 14–3-3β complex, leading to activation of the RAF1/MEK/ERK pathway. These findings suggest that SHBs prevents sorafenib-induced apoptosis in HCC cells by binding to PTPN1 and stimulating the formation of the PTPIP51/14–3-3β/RAF1 complex, thereby activating the RAF1/MEK/ERK signaling pathway. This mechanism provides insight into HBV-induced sorafenib resistance in HCC, highlighting SHBs as a potential target for overcoming treatment resistance in HBV-related HCC.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2471-2485"},"PeriodicalIF":4.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530615","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-Associated Neutrophils Regulate Breast Cancer Progression Through the AQP9/STAT3 Signaling Pathway 肿瘤相关中性粒细胞通过AQP9/STAT3信号通路调控乳腺癌进展

IF 4.3 2区医学

Cancer Science Pub Date : 2025-06-28 DOI: 10.1111/cas.70121

Wuqin Xu, Guilu Zhu, Youjing Sheng, Wenjun Zhang, Shujing Wang, Qiang Wu

{"title":"Tumor-Associated Neutrophils Regulate Breast Cancer Progression Through the AQP9/STAT3 Signaling Pathway","authors":"Wuqin Xu, Guilu Zhu, Youjing Sheng, Wenjun Zhang, Shujing Wang, Qiang Wu","doi":"10.1111/cas.70121","DOIUrl":"10.1111/cas.70121","url":null,"abstract":"Tumor-associated neutrophils (TANs) contribute to breast cancer (BC) progression, and aquaporin 9 (AQP9) plays a critical role in tumor development. However, the interactions between TANs and AQP9 in BC are poorly understood. Bioinformatics analyses and clinical samples revealed a positive correlation between neutrophil infiltration and AQP9 expression in BC. Treating BC cells with TAN-conditioned media significantly elevated AQP9 expression compared with neutrophil-conditioned and control media treatments. Immunohistochemical analysis revealed higher AQP9 protein expression in BC tissues than in adjacent normal tissues, and AQP9 expression was negatively correlated with recurrence-free survival and overall survival in patients with BC. Functional studies demonstrated that AQP9 promoted BC cell proliferation but did not affect migration or invasion. AQP9 knockdown markedly inhibited the ability of TANs to enhance BC cell proliferation, migration, and invasion. Intravenous and intratumoral injection of TANs in mice increased tumor growth rate, weight, and volume compared with controls; moreover, histological examination revealed lung metastasis in two mice and bone involvement in one mouse out of six in the TAN treatment group. AQP9 knockdown significantly reduced the tumor growth rate. In BC cells, TAN treatment elevated STAT3 phosphorylation, and this effect was amplified by AQP9 overexpression. In conclusion, TANs promote BC progression by enhancing STAT3 phosphorylation through AQP9 upregulation. AQP9 is crucial for TAN-mediated BC progression and is a potential target for immunotherapy in patients with BC.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2374-2387"},"PeriodicalIF":4.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530616","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