Cancer Science最新文献

{"title":"Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage","authors":"Enaam Alghamdi,&nbsp;Keiko Kono","doi":"10.1111/cas.70223","DOIUrl":"10.1111/cas.70223","url":null,"abstract":"<p>Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3274-3285"},"PeriodicalIF":4.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276376","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}

{"title":"COL6A2: A Key Survival-Related Gene and Restricting Antitumor Immunity in Glioblastoma","authors":"Zhenkun Yang,&nbsp;Jiao Meng,&nbsp;Daxing Xu,&nbsp;Jie Li,&nbsp;Fan Kong,&nbsp;Ying Yin,&nbsp;Bo Zhang,&nbsp;Yunhui Pan,&nbsp;Jiantong Jiao,&nbsp;Xinyi Jiang,&nbsp;Zhening Pu","doi":"10.1111/cas.70218","DOIUrl":"10.1111/cas.70218","url":null,"abstract":"<p>Glioblastoma (GBM) is an aggressive malignant brain tumor, characterized by a poor prognosis and a limited response to chemoradiotherapy and immunotherapy. Increasing evidence indicates that the extracellular matrix (ECM), particularly collagen proteins, contributes to tumor progression and immune evasion. In this study, we identified COL1A2, COL6A2, COL8A1, and COL8A2 as survival-related genes that were overexpressed in GBM and significantly upregulated in short-term survivors. Subsequently, COL6A2 was verified to be associated with chemotherapy and immunosuppression. Functional assays demonstrated that COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance. Cytometry by time-of-flight (CyTOF) and Tumor Immune Estimation Resource (TIMER) analysis revealed that high COL6A2 expression correlates with immunosuppressive features in the tumor microenvironment, particularly the accumulation of immature dendritic cells (DCs) and impaired cytotoxic T-cell activity. Mechanistically, COL6A2 silencing restored DCs' activation and enhanced the infiltration and function of effector immune cells. Our findings highlight COL6A2 as a key oncogenic and immunomodulatory ECM component in GBM and suggest that targeting collagen-mediated immune suppression may improve therapeutic outcomes in GBM patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3487-3502"},"PeriodicalIF":4.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276357","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}

{"title":"ACTN4 Gene Amplification and Actinin-4 Protein Expression for Osimertinib Efficacy in EGFR-Mutant NSCLC","authors":"Takehiro Tozuka,&nbsp;Rintaro Noro,&nbsp;Yutaka Naito,&nbsp;Nami Miura,&nbsp;Shinobu Kunugi,&nbsp;Kazufumi Honda,&nbsp;Masahiro Seike","doi":"10.1111/cas.70209","DOIUrl":"10.1111/cas.70209","url":null,"abstract":"<p>Actinin-4 (gene name: <i>ACTN4</i>) is an actin-bundling protein implicated in cancer invasion and metastasis. This study evaluated whether <i>ACTN4</i> amplification and actinin-4 protein expression were associated with osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer. We retrospectively analyzed 63 patients with epidermal growth factor receptor-mutant non-small cell lung cancer treated with osimertinib as first-line treatment. Immunohistochemistry was performed for pretreatment tumor tissues. Actinin-4 immunohistochemistry positivity was defined as positive staining of ≥ 30% tumor cells. In positive cases, <i>ACTN4</i> amplification was assessed via fluorescence in situ hybridization. Progression-free survival and overall survival were compared across groups. Among 63 patients (median age: 73 years, 52 with Eastern Cooperative Oncology Group performance status 0–1, 63 with adenocarcinoma; epidermal growth factor receptor mutations: 19del/L858R/uncommon = 32/24/7), there were 33 and 30 actinin-4 immunohistochemistry-positive and actinin-4 immunohistochemistry-negative cases, respectively. The propensity score-weighted overall survival and progression-free survival were significantly shorter for actinin-4 immunohistochemistry-positive patients than for actinin-4 immunohistochemistry-negative patients (overall survival: hazard ratio, 2.76; 95% confidence interval, 1.02–7.45; progression-free survival: hazard ratio, 1.91; 95% confidence interval, 1.03–3.54). Among the 33 actinin-4 immunohistochemistry-positive cases, four showed positivity in <i>ACTN4</i> fluorescence in situ hybridization. Overall survival and progression-free survival were numerically shorter for patients with <i>ACTN4</i> positivity than for those with <i>ACTN4</i> negativity in fluorescence in situ hybridization. The findings suggest that <i>ACTN4</i> amplification and actinin-4 protein expression are prognostic markers for poor osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3367-3375"},"PeriodicalIF":4.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276392","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}

{"title":"Zebrafish Xenograft Model for Predicting Cisplatin Efficacy in Muscle-Invasive Bladder Cancer","authors":"Yusuke Sugino,&nbsp;Xin Bao,&nbsp;Sho Sekito,&nbsp;Shiori Miyachi,&nbsp;Takumi Kageyama,&nbsp;Takeshi Sasaki,&nbsp;Kouhei Nishikawa,&nbsp;Toshio Tanaka,&nbsp;Manabu Kato,&nbsp;Yasuhito Shimada,&nbsp;Keishi Takano,&nbsp;Raku Son,&nbsp;Liqing Zang,&nbsp;Kenji Nakayama,&nbsp;Masatoshi Watanabe,&nbsp;Yasuhiro Murakawa,&nbsp;Takahiro Inoue","doi":"10.1111/cas.70217","DOIUrl":"10.1111/cas.70217","url":null,"abstract":"<p>The standard treatment for muscle-invasive bladder cancer (MIBC) is cisplatin (CDDP)-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy. However, only about 40% of patients respond to NAC, and tools to predict individual responses remain limited. The zebrafish patient-derived xenograft (zPDX) model offers a rapid and cost-effective platform for functional drug testing, but its application to MIBC has not yet been established. In this study, we developed a zPDX model optimized for evaluating CDDP sensitivity using clinical bladder cancer specimens. This model was validated through three steps: (1) evaluation of CDDP response in zPDXs derived from cell lines, (2) comparison of drug responses between mouse PDX (mPDX) and zPDX models, and (3) correlation of zPDX responses with clinical outcomes. The robustness of step 1 was demonstrated through complementary assays, including temperature optimization, in vivo platinum quantification, fluorescent dye validation, Cap Analysis of Gene Expression (CAGE), and whole-mount immunofluorescence. An image-based platform for quantifying drug response by measuring fluorescent area was established and applied in steps 2 and 3. Step 2, using mPDXs, provided essential technical validation before applying the protocol to clinical samples. In step 3, patient-derived tumors were transplanted into zebrafish, allowing successful prediction of CDDP efficacy. Despite the small patient cohort, this study provides fundamental evidence supporting zPDX as a clinically relevant and experimentally validated tool for functional assessment of CDDP sensitivity in bladder cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3376-3387"},"PeriodicalIF":4.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253311","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}

{"title":"Epigenetic Regulation of G6PD Drives Metabolic Reprogramming in Intrahepatic Cholangiocarcinoma","authors":"Yusuke Nakano,&nbsp;Miwa Tanaka,&nbsp;Takeharu Sakamoto,&nbsp;Masahiro Hashimoto,&nbsp;Taro Tobo,&nbsp;Hideyuki Saito,&nbsp;Tadashi Abe,&nbsp;Tomohiko Ikehara,&nbsp;Takashi Ofuchi,&nbsp;Koto Kawata,&nbsp;Takaaki Masuda,&nbsp;Takayuki Ogino,&nbsp;Mamoru Uemura,&nbsp;Hidetoshi Eguchi,&nbsp;Yuichiro Doki,&nbsp;Koshi Mimori","doi":"10.1111/cas.70202","DOIUrl":"10.1111/cas.70202","url":null,"abstract":"<p>Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with poor prognosis and significant molecular heterogeneity. This study investigates the role of tumor-specific enhancers in metabolic reprogramming, focusing on glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Using native elongating transcript–cap analysis of gene expression and single-cell RNA sequencing, tumor-specific enhancers driving G6PD overexpression were identified in ICC tumor epithelial cells. Functional assays demonstrated that G6PD promotes tumor proliferation by enhancing PPP activity and maintaining redox homeostasis, which provides NADPH to counter oxidative stress. Enhancer knockdown disrupted G6PD expression and PPP activity, increasing reactive oxygen species levels and reducing the NADPH/NADP⁺ ratio. These metabolic changes impaired tumor cell proliferation and sensitized ICC cells to cisplatin, emphasizing the dual therapeutic potential of targeting G6PD to inhibit tumor growth and overcome chemoresistance. Survival analyses showed that high G6PD expression correlates strongly with poor overall survival in ICC patients. While previous studies have recognized the roles of G6PD and PPP in cancer metabolism, this study uniquely links enhancer-mediated regulation to these processes in ICC, offering novel insights into epigenetic mechanisms driving metabolic reprogramming. Moreover, the findings highlight tumor-specific enhancers as critical epigenetic drivers of ICC progression, with potential as therapeutic targets. Future research should explore the integration of enhancer profiling into precision medicine frameworks and the development of novel enhancer-targeting strategies. These efforts could uncover additional metabolic vulnerabilities and provide effective treatments for this highly aggressive cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3352-3366"},"PeriodicalIF":4.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239976","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}

{"title":"Comparative Cytokine and Histology Studies on HPV and Other Viral Vaccinations: No Pathogenicity of HPV Vaccine Adjuvants","authors":"Reona Shiro,&nbsp;Fumitaka Sato,&nbsp;Seiichi Omura,&nbsp;Ah-Mee Park,&nbsp;Cong Thanh Nguyen,&nbsp;Ijaz Ahmad,&nbsp;Sandesh Rimal,&nbsp;Koji Kinoshita,&nbsp;Noriomi Matsumura,&nbsp;Ikuo Tsunoda","doi":"10.1111/cas.70213","DOIUrl":"10.1111/cas.70213","url":null,"abstract":"<p>In Japan, neuropsychological symptoms after human papillomavirus (HPV) vaccinations were publicized as “adverse effects,” leading to vaccine hesitancy. Anti-vaccine activists claimed that adjuvants in HPV vaccines could cause an immune-mediated neurological disease. Adjuvants in the bivalent HPV vaccine (2vHPV) and quadrivalent HPV vaccine (4vHPV) are AS04 [composed of aluminum (Al) hydroxide (AH) and monophosphoryl lipid A (MPL)] and Al hydroxyphosphate sulfate (AHS), respectively. We determined whether HPV vaccinations in mice could reproduce alleged immunopathology. We injected mice intramuscularly with 2vHPV, 4vHPV, two hepatitis B virus vaccines containing AH or AHS, or a varicella-zoster virus vaccine (vVZV) containing an adjuvant AS01 (comprising MPL and QS-21). Histologically, 12 weeks after vaccinations, all four Al-containing vaccine groups had Al-laden macrophage accumulation at the injected muscle; no groups had abnormalities in any other organs, including the brain, heart, liver, and kidney. Immunologically, although the four Al-containing vaccine groups had continuously increased levels of several cytokines, including interferon (IFN)-β, cytokine profiles were not associated with muscle pathology. No groups exhibited any clinical signs, except for the vVZV group, which lost body weight temporarily following each injection. Weight loss in the vVZV group was associated with increased levels of cytokines, including interleukin (IL)-18. Experiments using IL-18 receptor-deficient mice and AS01 injection alone demonstrated that IL-18 and AS01 contributed to weight loss. Since 2vHPV containing AS04 (AH and MPL) did not induce weight loss, QS-21, but not MPL, in AS01 seemed responsible for weight loss, demonstrating the safety of MPL.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3309-3325"},"PeriodicalIF":4.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233939","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}

{"title":"Emergence of PALB2 Reversion Mutations as a Mechanism of Resistance to Niraparib in Breast Cancer: A Case Report","authors":"Maako Kawamura,&nbsp;Hiroshi Tada,&nbsp;Hidekazu Shirota,&nbsp;Miki Dobashi,&nbsp;Noriko Takenaga,&nbsp;Hiroyuki Yasojima,&nbsp;Narumi Harada-shoji,&nbsp;Keigo Komine,&nbsp;Kenichi Nakamura,&nbsp;Minoru Miyashita,&nbsp;Hisato Kawakami","doi":"10.1111/cas.70210","DOIUrl":"10.1111/cas.70210","url":null,"abstract":"<p>This case study describes the clinical course of a 39-year-old woman with metastatic breast cancer harboring a germline PALB2 mutation who was treated with a PARP inhibitor. She initially demonstrated a clinical benefit with reduced tumor markers and favorable imaging findings. However, disease progression occurred after eight months. Liquid biopsy-based genomic profiling identified three PALB2 reversion mutations that restored homologous recombination, leading to treatment resistance. The case illustrates both the therapeutic potential of PARP inhibitors in PALB2-mutated cancers and the emergence of resistance. It emphasizes the importance of liquid biopsy-based genomic profiling for understanding tumor evolution and guiding treatment strategies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3540-3544"},"PeriodicalIF":4.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233981","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}

{"title":"IMPDH and GTP Metabolism in Cancer: Mechanisms, Regulation, and Translational Scope","authors":"Aki Ogawa-Iio,&nbsp;Koh Takeuchi,&nbsp;Keita Shigemi,&nbsp;Michelle Jane Genoveso,&nbsp;Hiroaki Niitsu,&nbsp;Iemasa Koh,&nbsp;Yusei Ota,&nbsp;Keita Yamane,&nbsp;Takao Hinoi,&nbsp;Natsuki Osaka,&nbsp;Masashi Oshima,&nbsp;Tomohiro Ishikawa,&nbsp;Tomoyuki Mizuno,&nbsp;Manabu Natsumeda,&nbsp;Kensuke Tateishi,&nbsp;Rintaro Hashizume,&nbsp;Satoru Osuka,&nbsp;Susumu Goyama,&nbsp;Tomoharu Yasuda,&nbsp;Toshiya Senda,&nbsp;Atsuo T. Sasaki","doi":"10.1111/cas.70200","DOIUrl":"10.1111/cas.70200","url":null,"abstract":"<p>Guanosine triphosphate (GTP) is increasingly recognized as a critical actor in cancer cell proliferation, yet its regulatory mechanism remains incompletely defined. A key contributor to elevated GTP levels in tumors is inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthetic pathway. Although IMPDH inhibitors, mycophenolic acid (MPA) and mycophenolate mofetil (MMF), have shown potential in cancer therapies, their success has been limited due to their immunosuppressive side effects and several unresolved regulatory mechanisms, including paradoxical control of IMPDH activity by GTP. This review provides a systematic summary of the current understanding of IMPDH biology, emphasizing its complex regulation and therapeutic relevance in cancer. We will outline key unresolved questions, including isozyme-specific roles and mechanisms for escaping regulation, and propose mechanistic and translational strategies to design IMPDH-targeted cancer therapies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3250-3265"},"PeriodicalIF":4.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214261","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}

{"title":"Deletion of the Mis12C-Binding Domain of CENP-C Promotes Chromosomal Aneuploidy in Cutaneous Squamous Cell Carcinoma","authors":"Megumi Saito,&nbsp;Kazuhiro Okumura,&nbsp;Yurika Tokunaga,&nbsp;Sora Tanaka,&nbsp;Keisuke Otoyama,&nbsp;Yoshinori Hasegawa,&nbsp;Masatoshi Hara,&nbsp;Masakazu Hashimoto,&nbsp;Toshihiko Fujimori,&nbsp;Tatsuo Fukagawa,&nbsp;Yuichi Wakabayashi","doi":"10.1111/cas.70216","DOIUrl":"10.1111/cas.70216","url":null,"abstract":"<p>CENP-C, an essential component of the kinetochore, connects centromeric chromatin to the outer kinetochore, and thereby ensures accurate chromosome segregation. Although deletion of the Mis12-binding domain (M12BD) of CENP-C does not cause developmental disorders in mice, it promotes malignant tumor progression in the two-stage DMBA/TPA-induced skin carcinogenesis model. In this study, we have demonstrated that M12BD deletion of CENP-C enhances proliferation and then promotes abnormal differentiation in DMBA/TPA-induced carcinomas in mice. To elucidate the underlying molecular mechanisms, we performed RNA sequencing and found the dysregulated expression of keratinization-related genes. Intriguingly, elevated chromosomal aneuploidy was detectable in mice with the M12BD deletion of CENP-C. Among the aneuploidies, trisomies of chromosomes 6 and 10 took place at the highest frequency. These specific chromosomal gains were accompanied by upregulation of genes involved in immune and inflammatory responses. Together, our present findings strongly suggest that M12BD of CENP-C plays a critical role in the regulation of epithelial differentiation during tumor development in mice.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3532-3539"},"PeriodicalIF":4.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226089","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}

{"title":"Reprimo (RPRM): A Tumor Suppressor That Induces Extrinsic Apoptosis via YAP Signaling","authors":"Masahiro Takikawa,&nbsp;Rieko Ohki","doi":"10.1111/cas.70215","DOIUrl":"10.1111/cas.70215","url":null,"abstract":"<p>Reprimo (encoded by <i>RPRM</i>) was initially identified as a p53 target gene in 2000 and functions as a tumor suppressor. Promoter hypermethylation of <i>RPRM</i> is frequently observed in various cancers, suggesting that it is transcriptionally silenced during tumorigenesis. Previous studies have reported that overexpression of <i>RPRM</i> induces G2/M cell cycle arrest, inhibits cell proliferation, promotes apoptosis, and increases cellular sensitivity to DNA damage. However, the molecular function of Reprimo is not completely understood. In particular, our recent studies revealed that Reprimo has a novel extracellular function, being secreted outside the cells where it functions to induce apoptosis in its target cells. Furthermore, we found that this apoptosis pathway is novel, mediated by a signaling pathway composed of p53-Reprimo-protocadherin family-Hippo-YAP/TAZ-p73. Reprimo is the first example of an extracellular ligand that induces cell death by modulating YAP activity and is a unique upstream regulator of Hippo signaling. This review summarizes current knowledge of the tumor-suppressive mechanisms of Reprimo, with an emphasis on its unique extracellular function and discusses potential future research directions and clinical applications in cancer therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 12","pages":"3266-3273"},"PeriodicalIF":4.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208145","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}