Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.
{"title":"mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer","authors":"Tomohiro Tamura , Shimpei Nagai , Kenta Masuda , Keiyo Imaeda , Eiji Sugihara , Juntaro Yamasaki , Miho Kawaida , Yuji Otsuki , Kentaro Suina , Hiroyuki Nobusue , Tomoko Akahane , Tatsuyuki Chiyoda , Iori Kisu , Yusuke Kobayashi , Kouji Banno , Kazuhiro Sakurada , Hajime Okita , Rui Yamaguchi , Ahmed Ashour Ahmed , Wataru Yamagami , Osamu Nagano","doi":"10.1016/j.canlet.2025.217565","DOIUrl":"10.1016/j.canlet.2025.217565","url":null,"abstract":"<div><div>Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in <em>BRCA1/2</em> wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217565"},"PeriodicalIF":9.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-16DOI: 10.1016/j.canlet.2025.217566
Xiang Xu , Zhixin Huang , Hui Han , Zihan Yu , Linying Ye , Zeyu Zhao , Yan Qian , Ying Li , Risheng Zhao , Tianhao Zhang , Yinan Liu , Junchao Cai , Shuibin Lin , Ertao Zhai , Jianhui Chen , Shirong Cai
N7-methylguanosine (m7G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m7G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m7G tRNA modifications in promoting GC progression. Upregulation of m7G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression in vitro and in vivo. Mechanistically, METTL1 knockdown reduces the expression of m7G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m7G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.
{"title":"N7-methylguanosine tRNA modification promotes gastric cancer progression by activating SDHAF4-dependent mitochondrial oxidative phosphorylation","authors":"Xiang Xu , Zhixin Huang , Hui Han , Zihan Yu , Linying Ye , Zeyu Zhao , Yan Qian , Ying Li , Risheng Zhao , Tianhao Zhang , Yinan Liu , Junchao Cai , Shuibin Lin , Ertao Zhai , Jianhui Chen , Shirong Cai","doi":"10.1016/j.canlet.2025.217566","DOIUrl":"10.1016/j.canlet.2025.217566","url":null,"abstract":"<div><div>N<sup>7</sup>-methylguanosine (m<sup>7</sup>G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m<sup>7</sup>G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m<sup>7</sup>G tRNA modifications in promoting GC progression. Upregulation of m<sup>7</sup>G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression <em>in vitro</em> and <em>in vivo</em>. Mechanistically, METTL1 knockdown reduces the expression of m<sup>7</sup>G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m<sup>7</sup>G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"615 ","pages":"Article 217566"},"PeriodicalIF":9.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-15DOI: 10.1016/j.canlet.2025.217545
Mingfang Guo , Misi He , Yun Dang , Li Lei , Qiaoling Li , Yue Huang , Liang Du , Haike Lei , Qian Zheng , Jing Wang , Xiuying Li , Hao He , Xiang Zhang , Ying Tang , Qi Zhou , Dongling Zou
Para-aortic lymph node (PALN) metastasis of patients with locally advanced cervical cancer (LACC) is associated with multiple risk factors. This study aimed to identify risk factors and develop a predictive model for PALN metastasis based on the pathological diagnosis via surgical staging to determine the patient-population suitable for extended-field irradiation (EFRT) and clarify the prognosis of patients with LACC. Five parameters were identified as predictors by logistic regression analysis. The predictive model was displayed as a nomogram and then modified into a simple scoring system. The concordance indices for the prediction nomogram were 0.939 in the training cohort, and 0.954 in the validation cohort, respectively. The scoring system consisted of tumor size, histological type, number of pelvic lymph nodes (PLNs), common iliac lymph node, and shorter diameter of the largest PLN. With a cutoff value of 8 points, the sensitivity and specificity of the predictive model were 91.04 % and 85.37 %, respectively, in the training cohort, and 89.47 % and 84.68 %, respectively, in the validation cohort. Using this system, patients were divided into high- and low-risk groups. Patients in the high-risk group showed a greater likelihood of PALN metastasis and worse PFS and OS than those in the low-risk group. The predictive model displays promise for the pathological diagnosis of PALN via surgical staging, offering good accuracy. It provides a non-invasive, practical tool to guide precise radiation strategy and stratify prognosis of patients with LACC.
{"title":"Predictors of para-aortic lymph node metastasis based on pathological diagnosis via surgical staging in patients with locally advanced cervical cancer: A multicenter study","authors":"Mingfang Guo , Misi He , Yun Dang , Li Lei , Qiaoling Li , Yue Huang , Liang Du , Haike Lei , Qian Zheng , Jing Wang , Xiuying Li , Hao He , Xiang Zhang , Ying Tang , Qi Zhou , Dongling Zou","doi":"10.1016/j.canlet.2025.217545","DOIUrl":"10.1016/j.canlet.2025.217545","url":null,"abstract":"<div><div>Para-aortic lymph node (PALN) metastasis of patients with locally advanced cervical cancer (LACC) is associated with multiple risk factors. This study aimed to identify risk factors and develop a predictive model for PALN metastasis based on the pathological diagnosis via surgical staging to determine the patient-population suitable for extended-field irradiation (EFRT) and clarify the prognosis of patients with LACC. Five parameters were identified as predictors by logistic regression analysis. The predictive model was displayed as a nomogram and then modified into a simple scoring system. The concordance indices for the prediction nomogram were 0.939 in the training cohort, and 0.954 in the validation cohort, respectively. The scoring system consisted of tumor size, histological type, number of pelvic lymph nodes (PLNs), common iliac lymph node, and shorter diameter of the largest PLN. With a cutoff value of 8 points, the sensitivity and specificity of the predictive model were 91.04 % and 85.37 %, respectively, in the training cohort, and 89.47 % and 84.68 %, respectively, in the validation cohort. Using this system, patients were divided into high- and low-risk groups. Patients in the high-risk group showed a greater likelihood of PALN metastasis and worse PFS and OS than those in the low-risk group. The predictive model displays promise for the pathological diagnosis of PALN via surgical staging, offering good accuracy. It provides a non-invasive, practical tool to guide precise radiation strategy and stratify prognosis of patients with LACC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217545"},"PeriodicalIF":9.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-15DOI: 10.1016/j.canlet.2025.217530
Donghee Kang , Jee Young Sung , Hyun Jung Hwang , Yurim Baek , Min-Ji Kim , Ga-Eun Lim , Yong-Nyun Kim , Jong-Ho Cha , Jae-Seon Lee
SF3B4, a splicing factor known to regulate mRNA expression and function, is upregulated in various cancers. Despite its potential significance, the mechanisms through which SF3B4 regulates nonsense-mediated mRNA decay (NMD) and cancer cell senescence remain poorly understood. This study explores the underlying mechanisms by which SF3B4 modulates mRNA stability through the NMD pathway and elucidates its role in switching cancer cells between growth and senescence. We demonstrate that SF3B4 deficiency leads to decreased cancer cell proliferation, increased senescence-associated β-galactosidase (SA-β-Gal) activity, p53-independent upregulation of p21 expression, and ultimate induction of cell senescence. We further show that SF3B4 recruits essential NMD factors, including UPF1, MAGOH, and RNPS1, which facilitate mRNA decay of the crucial senescence regulator, p21. Conversely, SF3B4 depletion results in the dissociation of these factors from the 3′UTR of p21 mRNA, thereby enhancing its stability. Collectively, our results suggest that SF3B4 critically regulates p21 expression at the post-transcriptional level, providing insights into the novel role of SF3B4 in regulating p21 mRNA stability, interacting with key NMD factors, and modulating cancer cell senescence.
{"title":"Splicing factor SF3B4 acts as a switch in cancer cell senescence by regulating p21 mRNA stability","authors":"Donghee Kang , Jee Young Sung , Hyun Jung Hwang , Yurim Baek , Min-Ji Kim , Ga-Eun Lim , Yong-Nyun Kim , Jong-Ho Cha , Jae-Seon Lee","doi":"10.1016/j.canlet.2025.217530","DOIUrl":"10.1016/j.canlet.2025.217530","url":null,"abstract":"<div><div>SF3B4, a splicing factor known to regulate mRNA expression and function, is upregulated in various cancers. Despite its potential significance, the mechanisms through which SF3B4 regulates nonsense-mediated mRNA decay (NMD) and cancer cell senescence remain poorly understood. This study explores the underlying mechanisms by which SF3B4 modulates mRNA stability through the NMD pathway and elucidates its role in switching cancer cells between growth and senescence. We demonstrate that SF3B4 deficiency leads to decreased cancer cell proliferation, increased senescence-associated β-galactosidase (SA-β-Gal) activity, p53-independent upregulation of p21 expression, and ultimate induction of cell senescence. We further show that SF3B4 recruits essential NMD factors, including UPF1, MAGOH, and RNPS1, which facilitate mRNA decay of the crucial senescence regulator, p21. Conversely, SF3B4 depletion results in the dissociation of these factors from the 3′UTR of p21 mRNA, thereby enhancing its stability. Collectively, our results suggest that SF3B4 critically regulates p21 expression at the post-transcriptional level, providing insights into the novel role of SF3B4 in regulating p21 mRNA stability, interacting with key NMD factors, and modulating cancer cell senescence.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"615 ","pages":"Article 217530"},"PeriodicalIF":9.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-14DOI: 10.1016/j.canlet.2025.217561
Xiayi Li , Xiaojing Yang , Shuchen Lin , Hui Cong , Yawen Liu , Yudong Wang , Jie Fu
Perineural invasion (PNI), the neoplastic infiltration of peripheral nerves, is recognized as the fourth mode of tumor metastasis and invasion. PNI is defined as a critical pathological feature observed across various cancers and is associated with poor prognosis. Recent studies have demonstrated that PNI also occurs in cervical cancer. Nerve-sparing radical hysterectomy (NSRH) has been promoted as the preferred approach for radical surgical resection of cervical cancer, as it reduces postoperative complications such as bladder, rectal, and sexual dysfunction. However, the presence of PNI has become a contraindication for NSRH. Despite the increasing volume of studies on PNI, the underlying mechanisms of its pathogenesis remain largely unclear. In this review, we discuss the innervation, characteristics, preoperative prediction and diagnosis of PNI in cervical cancer, along with its underlying mechanism, paving the way for advancements in treatment strategies and improving the prognosis for cervical cancer patients.
{"title":"Perineural invasion in cervical cancer","authors":"Xiayi Li , Xiaojing Yang , Shuchen Lin , Hui Cong , Yawen Liu , Yudong Wang , Jie Fu","doi":"10.1016/j.canlet.2025.217561","DOIUrl":"10.1016/j.canlet.2025.217561","url":null,"abstract":"<div><div>Perineural invasion (PNI), the neoplastic infiltration of peripheral nerves, is recognized as the fourth mode of tumor metastasis and invasion. PNI is defined as a critical pathological feature observed across various cancers and is associated with poor prognosis. Recent studies have demonstrated that PNI also occurs in cervical cancer. Nerve-sparing radical hysterectomy (NSRH) has been promoted as the preferred approach for radical surgical resection of cervical cancer, as it reduces postoperative complications such as bladder, rectal, and sexual dysfunction. However, the presence of PNI has become a contraindication for NSRH. Despite the increasing volume of studies on PNI, the underlying mechanisms of its pathogenesis remain largely unclear. In this review, we discuss the innervation, characteristics, preoperative prediction and diagnosis of PNI in cervical cancer, along with its underlying mechanism, paving the way for advancements in treatment strategies and improving the prognosis for cervical cancer patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217561"},"PeriodicalIF":9.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute myeloid leukemia (AML) with 3q26 rearrangements results in a poor prognosis and typically causes ecotropic viral integration site1 (EVI1) overexpression (EVI1oe); however, many AML patients with EVI1oe have undetected 3q26 rearrangements. The aim of this study was to restratify AML patients with EVI1oe. We retrospectively reviewed the diagnostic outcomes of 1327 patients tested at our institute from November 2015 to December 2022. A total of 468 de novo AML patients were included, with 191 classified as EVI1oe. Eighteen AML patients with EVI1oe had detectable 3q26 rearrangements and had significantly greater EVI1 expression levels than those without rearrangements. A new cutoff value for EVI1oe in AML patients of 122 % was determined using the ROC curve based on overall survival (OS) and effectively distinguished the prognosis of EVI1oe AML patients without detectable 3q26 rearrangements (p = 0.0051 and 0.0039, respectively). Using this cutoff value, ELN stratification, transplantation status, response to induction therapy, and bone marrow blast percentage, we constructed a nomogram model (C-index = 0.808). This model was used to stratify patients into two risk subgroups, with the low-risk subgroup showing better OS than the high-risk subgroup did (p < 0.001 in the training cohort; p = 0.002 in the validation cohort). In conclusion, AML patients with EVI1oe have heterogeneous prognoses. The use of EVI1 expression levels in combination with other risk factors may enable accurate prognostic stratification of AML patients with EVI1oe.
{"title":"The expression level of EVI1 and clinical features help to distinguish prognostic heterogeneity in the AML entity with EVI1 overexpression","authors":"Xiao-Hang Ma , Meng-Ge Gao , Rong-Qi Cheng , Ya-Zhen Qin , Wen-Bing Duan , Hao Jiang , Xiao-Jun Huang , Xiao-Su Zhao","doi":"10.1016/j.canlet.2025.217547","DOIUrl":"10.1016/j.canlet.2025.217547","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) with 3q26 rearrangements results in a poor prognosis and typically causes ecotropic viral integration site1 (<em>EVI1</em>) overexpression (<em>EVI1</em>oe); however, many AML patients with <em>EVI1</em>oe have undetected 3q26 rearrangements. The aim of this study was to restratify AML patients with <em>EVI1</em>oe. We retrospectively reviewed the diagnostic outcomes of 1327 patients tested at our institute from November 2015 to December 2022. A total of 468 de novo AML patients were included, with 191 classified as <em>EVI1</em>oe. Eighteen AML patients with <em>EVI1</em>oe had detectable 3q26 rearrangements and had significantly greater <em>EVI1</em> expression levels than those without rearrangements. A new cutoff value for <em>EVI1</em>oe in AML patients of 122 % was determined using the ROC curve based on overall survival (OS) and effectively distinguished the prognosis of <em>EVI1</em>oe AML patients without detectable 3q26 rearrangements (p = 0.0051 and 0.0039, respectively). Using this cutoff value, ELN stratification, transplantation status, response to induction therapy, and bone marrow blast percentage, we constructed a nomogram model (C-index = 0.808). This model was used to stratify patients into two risk subgroups, with the low-risk subgroup showing better OS than the high-risk subgroup did (p < 0.001 in the training cohort; p = 0.002 in the validation cohort). In conclusion, AML patients with <em>EVI1</em>oe have heterogeneous prognoses. The use of <em>EVI1</em> expression levels in combination with other risk factors may enable accurate prognostic stratification of AML patients with <em>EVI1</em>oe.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"615 ","pages":"Article 217547"},"PeriodicalIF":9.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-13DOI: 10.1016/j.canlet.2025.217539
Pierrick Martinez, Jean-Marc Sabatier
Cancer remains a significant global health challenge, with its progression shaped by complex and multifactorial mechanisms. Recent research suggests that the vagus nerve could play a critical role in mediating communication between the tumor microenvironment and the central nervous system (CNS). This review highlights the diversity of vagal afferent receptors, which could position the vagus nerve as a unique pathway for transmitting immune, metabolic, mechanical, and chemical signals from tumors to the CNS. Such signaling could influence systemic disease progression and tumor-related responses. Additionally, the vagus nerve's interactions with the microbiome and the renin-angiotensin system (RAS)-both implicated in cancer biology-further underscore its potential central role in modulating tumor-related processes. Contradictions in the literature, particularly concerning vagal fibers, illustrate the complexity of its involvement in tumor progression, with both tumor-promoting and tumor-suppressive effects reported depending on cancer type and context. These contradictions often overlook certain experimental biases, such as the failure to distinguish between vagal afferent and efferent fibers during vagotomies or the localized parasympathetic effects that cannot always be extrapolated to the systemic level. By focusing on the homeostatic role of the vagus nerve, understanding these mechanisms could open the door to new perspectives in cancer research related to the vagus nerve and lead to potential therapeutic innovations.
{"title":"Malignant Tumors in Vagal-innervated Organs: Exploring Its Homeostatic Role.","authors":"Pierrick Martinez, Jean-Marc Sabatier","doi":"10.1016/j.canlet.2025.217539","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217539","url":null,"abstract":"<p><p>Cancer remains a significant global health challenge, with its progression shaped by complex and multifactorial mechanisms. Recent research suggests that the vagus nerve could play a critical role in mediating communication between the tumor microenvironment and the central nervous system (CNS). This review highlights the diversity of vagal afferent receptors, which could position the vagus nerve as a unique pathway for transmitting immune, metabolic, mechanical, and chemical signals from tumors to the CNS. Such signaling could influence systemic disease progression and tumor-related responses. Additionally, the vagus nerve's interactions with the microbiome and the renin-angiotensin system (RAS)-both implicated in cancer biology-further underscore its potential central role in modulating tumor-related processes. Contradictions in the literature, particularly concerning vagal fibers, illustrate the complexity of its involvement in tumor progression, with both tumor-promoting and tumor-suppressive effects reported depending on cancer type and context. These contradictions often overlook certain experimental biases, such as the failure to distinguish between vagal afferent and efferent fibers during vagotomies or the localized parasympathetic effects that cannot always be extrapolated to the systemic level. By focusing on the homeostatic role of the vagus nerve, understanding these mechanisms could open the door to new perspectives in cancer research related to the vagus nerve and lead to potential therapeutic innovations.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217539"},"PeriodicalIF":9.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-13DOI: 10.1016/j.canlet.2025.217558
Yumei Huang , Anchen Qiu , Yimei Meng , Ming Lin , Yunhong Xu , Liu Yang
Radioresistance poses the main challenge in radiation therapy (RT) for liver cancer, with the DNA Damage response (DDR) being a crucial component of this resistance. Ubiquitin-conjugating enzyme E2O (UBE2O) has been implicated in regulating tumor proliferation, cholesterol metabolism, and drug resistance. However, the role of the ubiquitin-conjugating enzyme E2O (UBE2O) in DDR of liver cancer remains to be fully explored. We discovered an elevated expression of UBE2O within liver cancer tissues, which was notably associated with unfavorable prognoses in hepatocellular carcinoma (HCC) patients. Furthermore, we found that the suppression of UBE2O can effectively reduce the growth and resistance to radiotherapy of HCC cells in vitro and in vivo. Moreover, p90 ribosomal S6 kinase2 (RSK2) was confirmed as a novel interacting kinase of UBE2O, which mediated the phosphorylation and degradation of UBE2O at the Thr838 site. RSK2 inhibition promotes tumor proliferation and resistance to radiotherapy of HCC cells in vitro and in vivo, and these effects are abrogated upon UBE2O knockdown. Collectively, our work revealed that UBE2O promotes tumor progression and resistance to radiotherapy, which was negatively regulated by RSK2 for phosphorylation and degradation, indicating that the RSK2/UBE2O axis provides a potential radiosensitization target for HCC patients.
{"title":"RSK2-mediated phosphorylation and degradation of UBE2O inhibits hepatocellular carcinoma growth and resistance to radiotherapy","authors":"Yumei Huang , Anchen Qiu , Yimei Meng , Ming Lin , Yunhong Xu , Liu Yang","doi":"10.1016/j.canlet.2025.217558","DOIUrl":"10.1016/j.canlet.2025.217558","url":null,"abstract":"<div><div>Radioresistance poses the main challenge in radiation therapy (RT) for liver cancer, with the DNA Damage response (DDR) being a crucial component of this resistance. Ubiquitin-conjugating enzyme E2O (UBE2O) has been implicated in regulating tumor proliferation, cholesterol metabolism, and drug resistance. However, the role of the ubiquitin-conjugating enzyme E2O (UBE2O) in DDR of liver cancer remains to be fully explored. We discovered an elevated expression of UBE2O within liver cancer tissues, which was notably associated with unfavorable prognoses in hepatocellular carcinoma (HCC) patients. Furthermore, we found that the suppression of UBE2O can effectively reduce the growth and resistance to radiotherapy of HCC cells <em>in vitro</em> and <em>in vivo</em>. Moreover, p90 ribosomal S6 kinase2 (RSK2) was confirmed as a novel interacting kinase of UBE2O, which mediated the phosphorylation and degradation of UBE2O at the Thr838 site. RSK2 inhibition promotes tumor proliferation and resistance to radiotherapy of HCC cells <em>in vitro</em> and <em>in vivo</em>, and these effects are abrogated upon UBE2O knockdown. Collectively, our work revealed that UBE2O promotes tumor progression and resistance to radiotherapy, which was negatively regulated by RSK2 for phosphorylation and degradation, indicating that the RSK2/UBE2O axis provides a potential radiosensitization target for HCC patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"615 ","pages":"Article 217558"},"PeriodicalIF":9.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-13DOI: 10.1016/j.canlet.2025.217557
Huan Lin , Junjie Hua , Zhengze Gong , Mingwei Chen , Bingjiang Qiu , Yuxin Wu , Wenfeng He , Yumeng Wang , Zhengyun Feng , Yanting Liang , Wansheng Long , Ronggang Li , Qionglian Kuang , Yingxin Chen , Jiawei Lu , Shiwei Luo , Wei Zhao , Lixu Yan , Xin Chen , Zhenwei Shi , Zaiyi Liu
Lung adenocarcinoma (LUAD) has a heterogeneous prognosis and controversial postoperative treatment protocols. We aim to develop and validate a multimodal analysis framework that integrates CT images with H&E-stained whole-slide images (WSIs) to enhance risk stratification and predict adjuvant chemotherapy benefit in LUAD patients. We retrospectively collected data from 1039 resectable LUAD patients (stage I–III) across four centres, forming a training dataset (n = 303), two testing datasets (n = 197 and n = 228) for survival analysis, and a feature testing dataset (n = 311) for interpretability analysis. We extracted 487 tumour/peritumour radiomics features from CT images and 783 multiscale pathomics features from WSIs, characterising the shape of tumour (CT) and cancer nuclei (WSIs), as well as the intensity and texture of tumour/peritumour regions (CT) and tumour regions/epithelium/stroma (WSIs). A survival support vector machine (SVM) was employed to establish a radiopathomics signature using the optimal set of multimodal features, including 2 tumour radiomics features, 3 peritumour radiomics features, and 4 nuclei heterogeneity pathomics features. The radiopathomics signature outperformed both radiomics and pathomics signatures in predicting disease-free survival (DFS) (C-index: training dataset, 0.744 vs. 0.734 and 0.692; testing dataset 1, 0.719 vs. 0.701 and 0.638; testing dataset 2, 0.711 vs. 0.689 and 0.684), demonstrating greater robustness compared to the state-of-the-art deep learning integration approaches. It provided additional prognostic information beyond clinical risk factors (C-index of clinical plus radiopathomics vs. clinical models: training dataset, 0.763 vs. 0.676; testing dataset 1, 0.739 vs. 0.676; testing dataset 2, 0.711 vs. 0.699, p < 0.001). Compared to low-risk patients categorised by the radiopathomics signature, high-risk patients achieved comparable DFS when receiving adjuvant chemotherapy (training dataset, HR = 1.53, 95 % CI 0.85–2.73, p = 0.153; testing dataset 1 and 2, HR = 1.62, 95 % CI 0.92–2.85, p = 0.096), but had significantly worse DFS when only observed after surgery (training dataset, HR = 4.46, 95 % CI 2.82–7.05, p < 0.001; testing datasets 1 and 2, HR = 3.52, 95 % CI 2.26–5.49, p < 0.001), indicating the predictive value of the radiopathomics signature for adjuvant chemotherapy benefit (interaction p < 0.05). Further interpretability analysis revealed that the radiopathomics signature was associated with various prognostic/treatment-related biomarkers, including differentiation, immune phenotypes, and EGFR status. The multimodal integration framework offered a cost-effective approach for LUAD characterisation by leveraging complementary information from radiological and histopathological imaging. The radiopathomics signature demonstrated robust prognostic capabilities, providing valuable insights for postoperative treatment decisions.
{"title":"Multimodal radiopathological integration for prognosis and prediction of adjuvant chemotherapy benefit in resectable lung adenocarcinoma: A multicentre study","authors":"Huan Lin , Junjie Hua , Zhengze Gong , Mingwei Chen , Bingjiang Qiu , Yuxin Wu , Wenfeng He , Yumeng Wang , Zhengyun Feng , Yanting Liang , Wansheng Long , Ronggang Li , Qionglian Kuang , Yingxin Chen , Jiawei Lu , Shiwei Luo , Wei Zhao , Lixu Yan , Xin Chen , Zhenwei Shi , Zaiyi Liu","doi":"10.1016/j.canlet.2025.217557","DOIUrl":"10.1016/j.canlet.2025.217557","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) has a heterogeneous prognosis and controversial postoperative treatment protocols. We aim to develop and validate a multimodal analysis framework that integrates CT images with H&E-stained whole-slide images (WSIs) to enhance risk stratification and predict adjuvant chemotherapy benefit in LUAD patients. We retrospectively collected data from 1039 resectable LUAD patients (stage I–III) across four centres, forming a training dataset (n = 303), two testing datasets (n = 197 and n = 228) for survival analysis, and a feature testing dataset (n = 311) for interpretability analysis. We extracted 487 tumour/peritumour radiomics features from CT images and 783 multiscale pathomics features from WSIs, characterising the shape of tumour (CT) and cancer nuclei (WSIs), as well as the intensity and texture of tumour/peritumour regions (CT) and tumour regions/epithelium/stroma (WSIs). A survival support vector machine (SVM) was employed to establish a radiopathomics signature using the optimal set of multimodal features, including 2 tumour radiomics features, 3 peritumour radiomics features, and 4 nuclei heterogeneity pathomics features. The radiopathomics signature outperformed both radiomics and pathomics signatures in predicting disease-free survival (DFS) (C-index: training dataset, 0.744 vs. 0.734 and 0.692; testing dataset 1, 0.719 vs. 0.701 and 0.638; testing dataset 2, 0.711 vs. 0.689 and 0.684), demonstrating greater robustness compared to the state-of-the-art deep learning integration approaches. It provided additional prognostic information beyond clinical risk factors (C-index of clinical plus radiopathomics vs. clinical models: training dataset, 0.763 vs. 0.676; testing dataset 1, 0.739 vs. 0.676; testing dataset 2, 0.711 vs. 0.699, p < 0.001). Compared to low-risk patients categorised by the radiopathomics signature, high-risk patients achieved comparable DFS when receiving adjuvant chemotherapy (training dataset, HR = 1.53, 95 % CI 0.85–2.73, p = 0.153; testing dataset 1 and 2, HR = 1.62, 95 % CI 0.92–2.85, p = 0.096), but had significantly worse DFS when only observed after surgery (training dataset, HR = 4.46, 95 % CI 2.82–7.05, p < 0.001; testing datasets 1 and 2, HR = 3.52, 95 % CI 2.26–5.49, p < 0.001), indicating the predictive value of the radiopathomics signature for adjuvant chemotherapy benefit (interaction p < 0.05). Further interpretability analysis revealed that the radiopathomics signature was associated with various prognostic/treatment-related biomarkers, including differentiation, immune phenotypes, and EGFR status. The multimodal integration framework offered a cost-effective approach for LUAD characterisation by leveraging complementary information from radiological and histopathological imaging. The radiopathomics signature demonstrated robust prognostic capabilities, providing valuable insights for postoperative treatment decisions.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217557"},"PeriodicalIF":9.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-12DOI: 10.1016/j.canlet.2025.217556
Chengcheng Liu , Gexiu Liu , Fenling Zhou , Lu Chen , Boyang Chang , Hailin Tang , Hua Wang
B-cell acute lymphocytic leukemia (B-ALL) is a highly aggressive malignancy with poor prognosis. Developing diagnostic markers and therapeutic targets to identify and treat B-ALL early would improve the outcomes of B-ALL patients. Here, we conducted RNA next-generation sequencing using bone marrow (BM) specimens obtained from 7 B-ALL patients and 7 healthy donors. We found cysteine and glycine-rich protein 2 (CSRP2) upregulated in B-ALL. Down-regulation of CSRP2 resulted in suppressed cell proliferation and enhanced cell apoptosis in B-ALL. In addition, inhibition of CSRP2 increased cell ferroptosis in B-ALL cells. Mechanically, we revealed that transcription factor early B cell factor 1 (EBF1) regulated CSRP2 levels in B-ALL, and inhibition of EBF1 decreased CSRP2 levels in B-ALL. In conclusion, the dysregulation EBF1 led to CSRP2 upregulation and resulting in progression of B-ALL. The EBF1/CSRP2 axis could be of great potential as therapeutic targets for B-ALL treatment.
{"title":"EBF1-induced CSRP2 boosts the progression of B-cell acute lymphocytic leukemia by inhibiting ferroptosis","authors":"Chengcheng Liu , Gexiu Liu , Fenling Zhou , Lu Chen , Boyang Chang , Hailin Tang , Hua Wang","doi":"10.1016/j.canlet.2025.217556","DOIUrl":"10.1016/j.canlet.2025.217556","url":null,"abstract":"<div><div>B-cell acute lymphocytic leukemia (B-ALL) is a highly aggressive malignancy with poor prognosis. Developing diagnostic markers and therapeutic targets to identify and treat B-ALL early would improve the outcomes of B-ALL patients. Here, we conducted RNA next-generation sequencing using bone marrow (BM) specimens obtained from 7 B-ALL patients and 7 healthy donors. We found cysteine and glycine-rich protein 2 (CSRP2) upregulated in B-ALL. Down-regulation of CSRP2 resulted in suppressed cell proliferation and enhanced cell apoptosis in B-ALL. In addition, inhibition of CSRP2 increased cell ferroptosis in B-ALL cells. Mechanically, we revealed that transcription factor early B cell factor 1 (EBF1) regulated CSRP2 levels in B-ALL, and inhibition of EBF1 decreased CSRP2 levels in B-ALL. In conclusion, the dysregulation EBF1 led to CSRP2 upregulation and resulting in progression of B-ALL. The EBF1/CSRP2 axis could be of great potential as therapeutic targets for B-ALL treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217556"},"PeriodicalIF":9.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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