American journal of cancer research最新文献

{"title":"The differentiation and intervention strategies for acute kidney injury after or induced by immune checkpoint inhibitors.","authors":"Zijun Ding, Gaosi Xu","doi":"10.62347/JECH8448","DOIUrl":"https://doi.org/10.62347/JECH8448","url":null,"abstract":"<p><p>With the increasing popularity of immune checkpoint inhibitors (ICIs) in tumor treatment, the incidence of immune-related adverse events (irAEs), including acute kidney injury (AKI), is on the rise. Renal biopsy serves as the gold standard for determining the true etiology of AKI following ICIs administration; however, due to potential risks and associated losses with this procedure, comprehensive analysis of physiological data and predictive models are gradually being incorporated into clinical practice to differentiate AKI etiologies. These include criteria such as a ≥ 100% increase in serum creatinine (Scr) from baseline or a 50% increase accompanied by other pathological manifestations, renal replacement therapy (RRT), or absence of any other reasonable cause. Currently, cessation of ICIs and steroid therapy represent commonly employed treatment approaches; nevertheless, these strategies have inherent side effects and may not be feasible for certain patient populations, such as those with diabetes, posing challenges for clinicians. Recent studies have demonstrated that rituximab, mycophenolate mofetil (MMF), and infliximab can potentially replace steroid therapy in managing ICIs-induced AKI (ICIs-AKI), offering a novel therapeutic perspective. This review provides an overview of non-invasive methods for distinguishing between AKI following ICIs use and ICIs-AKI while discussing strategies for treating ICIs-AKI.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1480-1493"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of glycan-lectin interactions in the tumor microenvironment: immunosuppression regulators of colorectal cancer.","authors":"Wenbin Chen, Quanzhi Cheng, Na Li, Kaiming Gu, Hongmei Zhao, Heya Na","doi":"10.62347/WBJL4045","DOIUrl":"https://doi.org/10.62347/WBJL4045","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a common malignant tumour and a serious global health issue. Glycosylation, a type of posttranslational modification, has been extensively studied in relation to cancer growth and metastasis. Aberrant glycosylation alters how the immune system in the microenvironment perceives the tumour and drives immune suppression through glycan-binding receptors. Interestingly, specific glycan signatures can be regarded as a new pattern of immune checkpoints. Lectins are a group of proteins that exhibit high affinity for glycosylation structures. Lectins and their ligands are found on endothelial cells (ECs), immune cells and tumour cells and play important roles in the tumour microenvironment (TME). In CRC, glycan-lectin interactions can accelerate immune evasion promoting the differentiation of tumour-associated M2 macrophages, altering T cell, dendritic cell (DC), natural killer (NK) cell, and regulatory T (Treg) cell activity to modify the functions of antigen-presenting cells functions. Here, we review our current knowledge on how glycan-lectin interactions affect immune-suppressive circuits in the TME and discuss their roles in the development of more effective immunotherapies for CRC.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1347-1383"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SEMA6B promotes thyroid tumorigenesis and chemoresistance via WNT/β-catenin signaling in response to doxorubicin.","authors":"Xiaoyu Liu, Shaoyang Cai, Yanhao Yang, Shenghui Lin, Qunxiong Pan, Xiangjin Chen","doi":"10.62347/BIUC4913","DOIUrl":"https://doi.org/10.62347/BIUC4913","url":null,"abstract":"<p><p>Thyroid cancer (THCA) is the most common endocrine malignancy and typically has a favorable prognosis. However, aggressive subtypes, particularly anaplastic thyroid carcinoma, present significant treatment challenges due to their high metastatic potential and resistance to conventional therapies. Therefore, a better understanding of the underlying mechanisms is essential for improving treatment strategies. Herein, we aimed to investigate the role of SEMA6B in THCA progression and explore its associated molecular mechanisms. Differentially expressed genes (DEGs) in THCA was screened using RNA sequencing data from paired THCA and normal tissues of 10 patients. The expression and functional role of SEMA6B in THCA were further examined using datasets from TCGA and GEO. Functional assays were conducted to evaluate the effects of SEMA6B overexpression and knockout on THCA cell proliferation. <i>In vivo</i> xenograft assays were performed to validate these findings. Additionally, the impact of SEMA6B on the WNT/β-catenin signaling pathway was verified. SEMA6B was highly expressed in THCA and significantly associated with poor clinical outcomes. SEMA6B overexpression significantly increased cell proliferation and colony formation, whereas its knockout reduced cell proliferation and enhanced sensitivity to Doxorubicin. Mechanistically, SEMA6B was found to promote activation of the WNT/β-catenin signaling pathway. In conclusion, these data reveal a novel oncogenic role for the SEMA6B/WNT/β-catenin signaling pathway in THCA, providing new insights and potential avenues for therapeutic intervention.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1540-1558"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of doxycycline on mycoplasma pneumonia treatment and cancer prognosis in pediatric leukemia patients post-chemotherapy: a target trial emulation.","authors":"Jun Wen, Xiaoyan Xu, Yufei Su, Xuehao Qi, Qiang Fu, Mingjiang Chen, Xue Wang","doi":"10.62347/KGBQ9641","DOIUrl":"https://doi.org/10.62347/KGBQ9641","url":null,"abstract":"<p><strong>Background: </strong>Acute leukemia is the most common malignancy in children. While chemotherapy is effective, it significantly compromises immune function, leading to a high incidence of infectious complications, such as secondary pneumonia, particularly Mycoplasma pneumonia (MP). The treatment of infections in pediatric leukemia patients faces challenges such as antibiotic resistance and drug interactions during chemotherapy.</p><p><strong>Objective: </strong>This study aims to evaluate the therapeutic efficacy and safety of doxycycline in treating MP in pediatric leukemia patients post-chemotherapy, as well as it impact on chemotherapy continuity.</p><p><strong>Methods: </strong>This study employed a target trial emulation design using retrospective data from pediatric leukemia patients diagnosed with MP. Patients aged 12-17 years with confirmed leukemia and clinical evidence of pneumonia following chemotherapy were included. Doxycycline was compared to azithromycin and other empirical treatments. Follow-up assessments at 3 days, 5 days, 30 days, and 180 days evaluated fever resolution, radiological improvement, additional interventions, and adverse events. Statistical analyses included Kaplan-Meier survival analysis and Cox proportional hazards models.</p><p><strong>Results: </strong>In Trial 2, doxycycline demonstrated a significantly higher treatment success rate than other empirical treatments (87.72% vs. 73.13%, P = 0.013) and was associated with faster fever resolution (P = 0.048) and shorter time to chest X-ray improvement (P = 0.048). The 30-day survival rate was significantly higher in the Doxycycline group compared to other empirical treatments (100% vs. 91.04%, P = 0.019). Fewer patients require additional interventions such as ICU admission (P = 0.019). Furthermore, patients in the Doxycycline group had a significantly higher likelihood of completing chemotherapy without delays (84.21% vs. 59.70%, P = 0.01). In Trial 1, no significant differences were observed in treatment success rate, fever resolution time, hospitalization duration, or chemotherapy tolerance between Doxycycline and Azithromycin (P > 0.05).</p><p><strong>Conclusion: </strong>Doxycycline, as a broad-spectrum antibiotic, demonstrates efficacy comparable to azithromycin in treating MP with advantages in reducing chemotherapy-related delays, hospitalization duration, and the need for additional interventions. It enhances chemotherapy tolerance and continuity. Doxycycline may serve as an economical and effective alternative for managing post-chemotherapy infections in pediatric leukemia patients, especially in cases of antibiotic resistance or intolerance.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1790-1805"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microbiota in breast cancer: dysbiosis, microbial metabolites, and therapeutic implications.","authors":"Yan Liu, Haiyang Ning, Yifei Li, Yifan Li, Jinfeng Ma","doi":"10.62347/ZJCF2843","DOIUrl":"https://doi.org/10.62347/ZJCF2843","url":null,"abstract":"<p><p>The human microbiome plays a pivotal role in host health and disease, with emerging evidence underscoring its significant influence on the development and progression of breast cancer. Studies have revealed that dysbiosis in both the gut and breast tissue microbiota is strongly associated with an elevated risk of breast cancer. Distinct microbial profiles have been identified among healthy individuals, patients with benign breast conditions, and those with malignant tumors, with further variations observed across different ethnic groups and breast cancer subtypes. The complex interplay between breast cancer risk factors and microbial populations, coupled with the direct impact of microbial communities and their metabolites on inflammatory pathways and immune responses, underscores the importance of this field. Additionally, the interaction between gut microbiota and therapeutic modalities such as chemotherapy and radiotherapy is of particular interest, as these interactions can significantly influence treatment outcomes, either enhancing or diminishing efficacy. This review explores the effects of the Mediterranean diet, probiotics, prebiotics, and natural medicinal products on gut microbiota, emphasizing their potential as innovative therapeutic strategies. Notably, the use of engineered probiotics within the tumor microenvironment represents a promising frontier in breast cancer treatment. In conclusion, research on the human microbiome not only deepens our understanding of breast cancer pathogenesis but also lays the groundwork for the development of novel and targeted therapeutic interventions.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1384-1409"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of albumin-to-alkaline phosphatase ratio and CONUT score in rectal cancer patients undergoing XELOX-based chemotherapy: development of a nomogram-based predictive model.","authors":"Min Tang, Shuang Liu, Wenbo Li, Xi Peng, Yu Wang, Yinghua Chen, Dan Yang, Tingxiu Xiang, Zhongjun Wu","doi":"10.62347/HSDE2538","DOIUrl":"https://doi.org/10.62347/HSDE2538","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the prognostic significance of the albumin-to-alkaline phosphatase ratio (AAPR) and the Controlling Nutritional Status (CONUT) score in rectal cancer (RC) patients receiving XELOX-based chemotherapy, and to develop a nomogram for predicting recurrence risk.</p><p><strong>Methods: </strong>This retrospective study included 389 RC patients treated at the First Affiliated Hospital of Chongqing Medical University, along with an independent validation cohort of 120 patients. Clinical variables, including AAPR and CONUT were analyzed using Cox regression and cumulative incidence function curves. A nomogram was constructed and validated using calibration plots and time-dependent receiver operating characteristic (ROC) curves.</p><p><strong>Results: </strong>Both AAPR (HR = 0.073, P<0.001) and CONUT score (HR = 1.497, P<0.001) were identified as independent predictors of recurrence. Additional factors significantly associated with increased recurrence risk included TNM stage III, tumor size ≥5 cm, vascular invasion, and carcinoembryonic antigen (CEA) level ≥5 ng/ml. The nomogram demonstrated strong predictive performance with a C-index of 0.860 in the training cohort, and 0.835 in the validation cohort. Calibration plots showed excellent agreement between predicted and observed recurrence probabilities.</p><p><strong>Conclusions: </strong>AAPR and CONUT score are independent prognostic indicators for recurrence in RC patients treated with XELOX-based chemotherapy. The proposed nomogram, incorporating these variables, provides a reliable tool for individualized risk prediction and may support personalized treatment decision-making.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1578-1596"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the nexus of p53 and PD-L1: insights into immunotherapy resistance mechanisms in hepatocellular carcinoma.","authors":"Guoyuan Zhang, Gan Zhang, Yixuan Zhao, Yunyan Wan, Bin Jiang, Huaxiang Wang","doi":"10.62347/BRTO3272","DOIUrl":"https://doi.org/10.62347/BRTO3272","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer worldwide, continues to pose a substantial health challenge with limited treatment options for advanced stages. Despite progress in therapies such as surgery, transplantation, and targeted treatments, prognosis remains bleak for many patients. The advent of immunotherapy has revolutionized the landscape of advanced HCC treatment, offering hope for improved outcomes. However, its efficacy is limited, with a modest response rate of approximately 20% as a single-agent therapy, underscoring the urgent need to decipher mechanisms of immunotherapy resistance. Tumor protein 53 gene (<i>TP53</i>), a pivotal tumor suppressor gene, and Programmed death ligand 1 (PD-L1), a crucial immune checkpoint ligand, play central roles in HCC's evasion of immune responses. Understanding how tumor protein 53 (p53) influences PD-L1 expression and immune system interactions is essential for unraveling the complexities of immunotherapy resistance mechanisms. Elucidating these molecular interactions not only enhances our understanding of HCC's underlying mechanisms but also lays the foundation for developing targeted treatments that may improve outcomes for patients with advanced-stage liver cancer. Ultimately, deciphering the nexus of p53 and PD-L1 in immunotherapy resistance promises to advance treatment strategies and outcomes in the challenging landscape of HCC. This review delves into the intricate relationship between p53 and PD-L1 concerning immunotherapy resistance in HCC, offering insights that could pave the way for novel therapeutic strategies aimed at enhancing treatment efficacy and overcoming resistance in advanced stages of the disease.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1410-1435"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disulfiram potentiates cisplatin-induced apoptosis in small cell lung cancer via the inhibition of cystathionine β-synthase and H₂S.","authors":"Yongguang Wang, Ruiping Du, Rong Gao, Chang Guo, Jian Qi, Yani Zhang, Qizhi Zhu, Qingmei Deng, Zongtao Hu, Hongzhi Wang, Bo Hong","doi":"10.62347/QJHB2816","DOIUrl":"https://doi.org/10.62347/QJHB2816","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is a highly malignant neuroendocrine tumor. Platinum-based chemo-resistance is the major issue for the treatment of SCLC. The objective of the study is to identify the drugs that enhance anti-tumor activity of cisplatin (CDDP) in SCLC. Firstly, by a high-throughput drug screening, we found that disulfiram (DSF), a FDA-approved drug that is used to treat alcohol addiction, was able to sensitize CDDP-induced apoptosis in SCLC. RNA-seq analysis revealed that cystathionine β-synthase (CBS) was a potential target of combination treatment of DSF and CDDP in SCLC. CDDP treatment induced CBS expression, while the elevation of CBS expression was down-regulated by DSF and CDDP co-treatment in SCLC. Importantly, the down-regulation of CBS by siRNA silence increased CDDP-induced cellular apoptosis in SCLC. Furthermore, the study found that DSF combined with CDDP decreased the H₂S level, and increased the level of ROS. The elevation of H₂S level reduced the growth inhibition of SCLC cells by DSF and CDDP co-treatment. Finally, in nude mice bearing SCLC xenografts, DSF and CDDP co-treatment exhibited remarkable anti-tumor activity against SCLC tumors, evidenced by the significant reduction of tumor size, tumor weight and Ki-67 expression as compared with single treatment alone. Therefore, the study indicated that DSF could be re-purposed to potentiate CDDP-induced anti-tumor activity in SCLC, which are worth immediate assessment for SCLC in clinical settings.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1647-1661"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of gamma knife stereotactic radiotherapy on the hematological system in patients with advanced lung cancer and its therapeutic effect.","authors":"Chun-Guang Ling, Jian-Feng Chen, Xiao-Chen Wang","doi":"10.62347/KMWI9314","DOIUrl":"https://doi.org/10.62347/KMWI9314","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the influence of Gamma Knife stereotactic body radiotherapy (SBRT) on the hematological system in patients with advanced lung cancer and to assess its clinical outcomes.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on the clinical data of 192 patients with advanced lung cancer. 108 patients who received conventional radiotherapy were included in the control group, and the rest 84 patients who received Gamma Knife SBRT were included in the experimental group. Treatment outcomes, disease progression one year after radiotherapy, blood cell counts, coagulation function, quality of survival scores, and adverse reactions were compared between the two groups.</p><p><strong>Results: </strong>The experimental group exhibited a significantly higher disease control rate (DCR) and objective response rate (ORR) compared to the control group (both <i>P</i><0.05). Radiotherapy modality was identified as an independent factor influencing disease progression within one year. Both groups experienced reductions in leukocytes, neutrophils, lymphocytes, erythrocytes, and platelets after radiotherapy, but the experimental group had less pronounced reductions (<i>P</i><0.05). Alterations in blood cell morphology were observed in both groups, with the experimental group showing fewer alterations (P<0.05). Coagulation function tests indicated a rise in prothrombin time (PT), a decrease in activated partial thromboplastin time (APTT), and an increase in fibrinogen (Fib) and D-Dimer (D-D) levels in both groups, with more favorable coagulation indices observed in the experimental group. Patients in both groups showed improvement in quality of survival scores post-treatment, with the experimental group outperforming the control group (<i>P</i><0.05). The incidence of adverse reactions was lower in the experimental group compared to the control group (<i>P</i><0.05).</p><p><strong>Conclusion: </strong>Compared to traditional radiotherapy, Gamma Knife SBRT has a less detrimental impact on the blood cell level, morphology, and coagulation function in patients with moderate to advanced lung cancer. It also improves patients' quality of survival with fewer adverse reactions and better disease control. These findings suggest that Gamma Knife SBRT is a promising treatment option and warrants further exploration and adoption in clinical practice.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1777-1789"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STOML2 inhibits sorafenib-induced ferroptosis in hepatocellular carcinoma via p-AKT signaling pathway.","authors":"Ruiqi Yin, Yifeng Tao, Jiahao Han, Jubo Zhang, Kangkang Yu, Yahui Zheng, Xiaoqi Li, Chong Huang","doi":"10.62347/SUTJ3506","DOIUrl":"https://doi.org/10.62347/SUTJ3506","url":null,"abstract":"<p><p>Tyrosine kinase inhibitor resistance is a key factor affecting the prognosis of patients with advanced hepatocellular carcinoma (HCC). Previously, our group demonstrated that HCC patients with high stomatin-like protein 2 (STOML2) expression were poorly sensitive to systemic therapy. Whether STOML2 is involved in sorafenib resistance is unclear. Recent mechanistic studies have demonstrated that selective activation of ferroptosis pathways is expected to restore sorafenib sensitivity. The aim of the present study was to investigate the STOML2-ferroptosis axis and its contribution to sorafenib resistance. In this study, STOML2 expression was detected in tissue microarrays from patients with primary HCC and in human cell lines. Functional proliferative clone formation assay was used to study the biological function of STOML2. Ferroptosis was detected by flow cytometry, cellular lipid peroxidation and the malondialdehyde (MDA) test. Western blotting and qPCR assays were used to verify the STOML2-AKT-solute carrier family 7 membrane 11 (SLC7A11) axis and to explore the possible mechanism of the combination of LY294002 (an AKT inhibitor) in patients with advanced HCC. The results indicated that patients with poor efficacy demonstrated higher expression of STOML2 compared with that in samples derived from patients with good efficacy. Knockdown of STOML2 expression inhibited colony formation and IC₅₀ in HCC cell lines treated with sorafenib. High STOML2 expression was negatively correlated with ferroptosis as shown by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. STOML2 inhibited ferroptosis by activating the AKT-SLC7A11 axis, which promoted increased intracellular antioxidant capacity. The AKT inhibitor LY294002 exhibited synergistic antitumor effects with sorafenib in HCC. In conclusion, the present study demonstrated that STOML2 could enhance the AKT-SLC7A11-mediated antioxidant capacity in HCC, inhibit ferroptosis and reduce the sensitivity of HCC to sorafenib, providing a theoretical basis for the combination of LY294002 and sorafenib.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 4","pages":"1614-1628"},"PeriodicalIF":3.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}