American journal of cancer research最新文献

{"title":"Aurora-A inhibits hepatocellular carcinoma cell ferroptosis to mediate immune escape by disrupting phosphatidylethanolamine biosynthesis.","authors":"Lei Fan, Yiqian Liu, Yucheng Cai, Xinnan Sun, Jiaxuan Li, Yiyang Xu, Changchun Sun, Shiyun Cui","doi":"10.62347/JTQO8098","DOIUrl":"10.62347/JTQO8098","url":null,"abstract":"<p><p>This study aims to explore Aurora-A's role in regulating immune escape of hepatocellular carcinoma (HCC). We performed non-targeted metabolomics analysis and analyzed the impact of Aurora-A inhibitor Alisertib on anti-PD-1 therapy efficacy on xenograft tumors and co-culture models of CD8⁺ T cells and HCC cells. We determined reactive oxygen species (ROS) and malondialdehyde (MDA) production in HCC cells to evaluate lipid peroxidation. Confocal images of endoplasmic reticulum (ER) and mitochondria in HCC cells were taken to assess the role of Aurora-A and dynamin-related protein 1 (Drp-1) on mitochondria-associated endoplasmic reticulum membranes (MAMs) formation. The results showed that Aurora-A was upregulated in HCC cells and its knockdown significantly augmented phosphatidylethanolamine (PE) production while having no effect on phosphatidylserine decarboxylase (PSD). Further, Aurora-A inhibitor Alisertib enhanced the sensibility of HCC cells to anti-PD-1 therapy and CD45⁺CD8⁺ T cell infiltration in HCC tumors. To conclude, our work revealed that Aurora-A dysregulated PS/PE metabolism via facilitating Drp1-Ser616 phosphorylation to disrupt MAMs formation, resulting in suppressed ferroptosis in HCC cells to reduce their sensitivity to anti-PD-1.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3693-3711"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063081","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":"Placental mesenchymal stem cell-derived interleukin-6 promotes neuroblastoma progression.","authors":"Ying Liu, Bai Li, Huixia Wei, Yan Xu, Yufeng Liu","doi":"10.62347/KNYX4079","DOIUrl":"10.62347/KNYX4079","url":null,"abstract":"<p><p>Neuroblastoma (NB) is a prevalent pediatric malignancy, yet the role of mesenchymal stem cells (MSCs) in NB progression remains unclear. MSCs are known to secrete various cytokines, including interleukin (IL)-6, and their influence on NB cells and tumor xenografts were investigated in this study. Placenta-derived mesenchymal stem cells (PMSCs) were isolated from chorionic villi and characterized via flow cytometry. The obtained PMSCs were co-cultured with NB cells or IL-6-silenced PMSCs. Comprehensive assays were conducted to assess proliferation, colony formation, cell cycle progression, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT). RNA-seq identified differentially expressed genes (DEGs) in NB cells, predominantly enriched in Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways (P < 0.05). qRT-PCR revealed elevated levels of IL-6 and other oncogenic cytokines in PMSCs (P < 0.05). In vivo, IL-6 knockdown in PMSCs significantly suppressed NB xenograft growth, accompanied by reduced expression of Ki-67, proliferating cell nuclear antigen (PCNA), Caspase 9, and Snail as shown by immunohistochemistry (P < 0.05). Western blotting confirmed activation of phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) pathway in NB cells after co-culture with PMSCs, which was attenuated by PI3K inhibition. Notably, IL-6 knockdown markedly suppressed NB xenograft progression and downregulated associated signaling markers (P < 0.05). Collectively, PMSC-derived IL-6 potentiates NB progression via PI3K-AKT signaling, presenting a potential therapeutic target in neuroblastoma.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3712-3727"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063262","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":"Effects of liposomal bupivacaine for erector spinae plane block on perioperative immune function and analgesia in thoracoscopic lung cancer surgery.","authors":"Chenghai Wang, Baosheng Zheng, Changsen Lin, Xikai Li, Ruxia Li, Luxi Zhao, Shijin Liu, Huimei Hao","doi":"10.62347/SQHE7607","DOIUrl":"10.62347/SQHE7607","url":null,"abstract":"<p><strong>Objective: </strong>To assess the immunomodulatory and analgesic effects of liposomal bupivacaine compared to ropivacaine on erector spinae plane block (ESPB) for patients undergoing thoracoscopic lung cancer surgery.</p><p><strong>Methods: </strong>This retrospective study included 260 patients undergoing thoracoscopic lung cancer surgery. Patients were divided into two groups based on anesthesia methods: the liposomal bupivacaine group (n = 134) and the ropivacaine group (n = 126). Both groups received general anesthesia followed by ESPB. Perioperative inflammatory markers (IL-6, TNF-α, CRP), immunoglobulins (IgA, IgG, IgM), and analgesic outcomes (Numerical Rating Scale (NRS) scores) were measured at various postoperative time points. Cellular inflammatory markers, including white blood cell (WBC) counts and neutrophil percentages, were also assessed. Tumor markers (galectin-3 (Gal-3), carbohydrate antigen 125 (CA125), cytokeratin 21-1 fragment (CY-FRA21-1), soluble programmed death ligand-1 (sPD-L1)) were analyzed at 3-month follow-up.</p><p><strong>Results: </strong>The liposomal bupivacaine group exhibited significantly reduced inflammatory responses with lower levels of IL-6 (P = 0.005), TNF-α (P = 0.007), and CRP (P = 0.01) at 12-72 hours postoperatively. Immunoglobulin levels were better preserved in this group (IgA P = 0.007, IgG P = 0.016, IgM P = 0.033). Analgesia outcomes were superior, with lower NRS scores at 36 h (P = 0.002) and 72 h (P = 0.006). Cellular inflammatory markers, including WBC counts and neutrophil percentages, were also significantly reduced (P < 0.05). At the 3-month follow-up, the liposomal bupivacaine group showed significantly lower levels of tumor markers, particularly sPD-L1 (all P < 0.001).</p><p><strong>Conclusions: </strong>Liposomal bupivacaine for ESPB enhances both immunoprotective effects and postoperative analgesia in thoracoscopic lung cancer surgery.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3728-3739"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063150","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":"WTAP-mediated m6A regulation in digestive system cancers: from molecular mechanisms to therapeutic strategies.","authors":"Dingge Cao, Mingzhen Wang, Yunyang Wang, Xueqing Hong, Xujun Liu, Wenzhe Si","doi":"10.62347/XYKG2252","DOIUrl":"10.62347/XYKG2252","url":null,"abstract":"<p><p>Epigenetic modifications, particularly RNA methylation, play a crucial role in cancer progression, and N6-methyladenosine (m6A) is the most prevalent mRNA modification in eukaryotes. Wilms tumor 1-associated protein (WTAP), a key component of the m6A methyltransferase complex (MTC), regulates m6A modification, influencing RNA stability, translation, and degradation. WTAP dysregulation has been implicated in various malignancies, with particularly significant roles observed across the digestive system cancers, including but not limited to esophageal, gastric, pancreatic, gallbladder, hepatocellular, and colorectal carcinomas. Overexpression of WTAP is frequently associated with poor prognosis, advanced tumor stages, and increased metastatic potential. This review highlights the multifaceted roles and regulatory network of WTAP in digestive system cancers (DSCs) progression, encompassing tumor cell proliferation, migration, invasion, drug resistance, and immune evasion. Targeting WTAP may offer novel therapeutic strategies for overcoming therapy resistance and improving clinical outcomes in digestive system malignancies. Future research should prioritize: (1) validation of these findings in larger, multicenter, and ethnically diverse patient cohorts; (2) comprehensive elucidation of the molecular mechanisms underlying WTAP-mediated regulation in cancer biology; and (3) systematic exploration of its functional consequences in tumor progression and therapy resistance.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3661-3677"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063099","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":"Comparative effectiveness of perioperative strategies for resectable gastric and gastroesophageal junction cancer: a Bayesian network meta-analysis.","authors":"Limin Chi, Mengyan Li, Hanxing Zhou, Wei-Jan Wang, Bo Wang, Xian Sun","doi":"10.62347/ECKT5511","DOIUrl":"10.62347/ECKT5511","url":null,"abstract":"<p><p>Perioperative strategies for resectable gastric and gastroesophageal junction (GEJ) adenocarcinomas are continuously evolving, with recent regimens, particularly those incorporating immunotherapy, showing promising results, although their comparative efficacy remains uncertain. We conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) published between January 2004 and March 2025 that compared perioperative treatments involving chemotherapy, radiotherapy, immunotherapy, or targeted agents. Five outcomes were analyzed: overall survival (OS), progression-free survival (PFS), R0 resection, pathological complete response (pCR), and major pathological response (MPR). A Bayesian random-effects model was applied to estimate hazard ratios (HRs) and odds ratios (ORs), and surface under the cumulative ranking curve (SUCRA) values were used for treatment ranking. A total of 25 RCTs involving 11,317 patients were included. Neo/Peri DOS/DOX, comprising neoadjuvant or perioperative docetaxel-oxaliplatin-S-1 (DOS) or docetaxel-oxaliplatin-capecitabine (DOX), ranked highest for OS and PFS, showing significant survival benefits over both surgery alone and adjuvant chemotherapy. Regimens combining perioperative chemotherapy with PD-1/PD-L1 inhibitors (Neo/Peri CT+PD1/PDL1) achieved the greatest improvement in pCR and MPR, although their survival benefit was limited to comparisons with surgery alone. None of the regimens significantly improved R0 resection. The findings were robust across sensitivity analyses, with no major inconsistencies detected. In conclusion, DOS/DOX demonstrated superior survival outcomes and may represent a leading perioperative option, while PD-1/PD-L1-based combinations improved early pathological responses but require further validation with mature survival data.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3781-3794"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063128","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":"Enhanced anticancer activity of novel pyrimidine nucleoside analog in pancreatic cancer.","authors":"Raviteja Bulusu, Joy Okoro, Esther Frimpong, Sunil Krishnan, Saunjoo Yoon, Bo Han, Xue Zhu, Edward Agyare","doi":"10.62347/ARCZ1924","DOIUrl":"10.62347/ARCZ1924","url":null,"abstract":"<p><p>This study explores the synthesis, characterization, and therapeutic efficacy of AGY₁, AGY₂, AGY₃, AGY₄, and AGY₅, which are novel 5-FU analogs designed to improve metabolic stability, prolong half-life, and anti-tumor activity against pancreatic cancer. The 5-FU molecule was chemically modified to bypass dihydropyrimidine dehydrogenase (DPD)-mediated inactivation, enhancing drug retention and increasing lipophilicity for improved cellular uptake. The analog cytotoxic activity was evaluated in 2D monolayer cultures and 3D pancreatic cancer spheroids and organoid models derived from MiaPaCa-2 and PANC-1 cells to simulate a more complex tumor environment. In the 2D model, AGY₁, AGY₂, AGY₃, AGY₄, and AGY₅ displayed significantly higher cytotoxicity than 5-FU, with AGY₂ achieving up to six-fold higher potency in MiaPaCa-2 cells. In 3D spheroid models, both AGY₁ and AGY₂ showed dose-dependent reductions in spheroid size, with AGY₂ causing the most pronounced shrinkage, suggesting effective disruption of the tumor architecture. In pancreatic organoids, AGY₂ demonstrated substantial decreases in cell viability and structural proliferation, inhibiting cell migration and organoid budding that exceeded the effects of 5-FU. Furthermore, cell cycle analysis revealed that AGY₂ induces significant cell cycle arrest at the G0/G1 phase in MiaPaCa-2 cells and the S phase in PANC-1 cells. Apoptosis assays showed a higher percentage of apoptotic cells following AGY₂ treatment compared to 5-FU, which was supported by Western blot analysis, indicating increased expression of pro-apoptotic proteins p53 and Bax and decreased levels of survival proteins epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), and Poly (ADP-ribose) polymerase (PARP). Put together, our findings showed that AGY₂ analog was the most effective anti-anticancer analog with significantly improved metabolic stability.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3740-3761"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063116","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":"Multivariate analysis and prediction model construction for distant metastasis of Acral Melanoma.","authors":"Jiabin Deng, Mengru Gao, Hailin Yao, Junjun Wu, Lei Cui, Xiaojing Li","doi":"10.62347/OLPB3585","DOIUrl":"10.62347/OLPB3585","url":null,"abstract":"<p><strong>Objective: </strong>To analyze the pathological characteristics of Acral Melanoma (AM) patients and identify the factors influencing distant metastasis, while constructing a predictive model for distant metastasis-free survival (DMFS).</p><p><strong>Methods: </strong>Conducted on 229 AM patients admitted to the Third People's Hospital of Bengbu and The First Affiliated Hospital of Anhui Medical University from January 1, 2012, to December 31, 2024. Data collected included gender, age, lesion location, initial diagnosis stage, trauma history, ulcer presence, Breslow thickness, mitotic rate, lactate dehydrogenase (LDH), albumin (Alb), and adjuvant therapy. DMFS was assessed through follow-up, with a deadline of March 31, 2025. Statistical analysis was performed to evaluate significant factors influencing distant metastasis.</p><p><strong>Results: </strong>The incidence of AM showed an increasing trend from 2012 to 2024. Of the 229 patients, 78 (34.06%) developed distant metastasis. The median follow-up period was 37 months, and 1-year, 3-year, and 5-year survival rates without distant metastasis were 93.45%, 74.24%, and 66.81%, respectively. Statistically significant factors affecting DMFS included initial diagnosis stage, ulcer presence, Breslow thickness, mitotic rate, LDH, and Alb levels (all P<0.05). Risk factors for distant metastasis included stage III at diagnosis, ulcer presence, lack of adjuvant therapy, elevated LDH, and low Alb levels.</p><p><strong>Conclusions: </strong>The study identified key pathological factors influencing distant metastasis in AM patients. The constructed nomogram model demonstrated good predictive accuracy, with AUC values of 0.895 and 0.879 in the training and validation sets, respectively. This model can aid in the clinical screening of AM patients at risk for distant metastasis.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3678-3692"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063198","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":"Erratum: HMGA2 regulates CD44 expression to promote gastric cancer cell motility and sphere formation.","authors":"Junying Sun, Baocun Sun, Dongwang Zhu, Xiulan Zhao, Yanhui Zhang, Xueyi Dong, Na Che, Jing Li, Fang Liu, Nan Zhao, Danfang Zhang, Tieju Liu, Xian Lin","doi":"10.62347/HRCT8829","DOIUrl":"10.62347/HRCT8829","url":null,"abstract":"<p><p>[This corrects the article on p. 260 in vol. 7, PMID: 28337375.].</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3808-3812"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063092","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":"Thalidomide combined with ifosfamide significantly improves survival in patients with pulmonary metastatic osteosarcoma.","authors":"Yuanxiang Liu, Huabin Wang, Zhengkai Xiang","doi":"10.62347/AEWT1662","DOIUrl":"10.62347/AEWT1662","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the efficacy and safety of thalidomide combined with ifosfamide (IFO) in the treatment of pulmonary metastatic osteosarcoma and to compare its outcomes with the IFO plus etoposide (ETOP) regimen, providing a reference for the clinical treatment of osteosarcoma.</p><p><strong>Methods: </strong>In this retrospective study, clinical data from 95 patients with pathologically confirmed osteosarcoma were analyzed. Of these, 55 patients received thalidomide + IFO (Observation group), and 40 patients received IFO + ETOP (Control group). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions (ARs) were compared between the two groups.</p><p><strong>Results: </strong>After treatment, the maximum diameters of both primary tumors and lung metastatic (LM) lesions in the Observation group were significantly smaller than those in the Control group. The median PFS was 10 months in the Observation group and 7.5 months in the Control group; the median OS was 22 months in the Observation group and 14 months in the Control group. The ORR and DCR in the Observation group were 23.63% and 52.73%, both significantly higher than those in the Control group (P<0.05). The incidences of hematological toxicity, gastrointestinal reactions, and renal dysfunction were significantly lower in the Observation group than in the Control group (<i>P</i><0.05). Multivariate Cox regression analysis identified number of pulmonary metastases (HR=1.256, <i>P</i>=0.038), T stage (HR=1.453, <i>P</i>=0.033), N stage (HR=1.389, <i>P</i>=0.035), receipt of radiotherapy (HR=1.589, <i>P</i>=0.018), and LDH levels (HR=1.356, <i>P</i>=0.015) as independent prognostic factors for pulmonary metastatic osteosarcoma.</p><p><strong>Conclusion: </strong>Thalidomide + IFO notably improves PFS and OS in patients with pulmonary metastatic osteosarcoma, demonstrating superior safety compared with the IFO-ETOP regimen.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3795-3807"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063107","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":"Hypoxia-anoikis-related genes in LUAD: machine learning and RNA sequencing analysis of immune infiltration and therapy response.","authors":"Yihao Liu, Wenhao Zhao, Zexia Zhao, Zhixuan Duan, Hua Huang, Chen Ding, Sensen Hou, Minghui Liu, Hongbing Zhang, Yongwen Li, Min Wang, Wenjun Meng, Jun Chen, Haoling Zhang, Honglin Zhao","doi":"10.62347/GQVA7530","DOIUrl":"10.62347/GQVA7530","url":null,"abstract":"<p><p>Hypoxia plays a crucial role in the pathogenesis of various cancers, especially lung adenocarcinoma (LUAD), by altering cancer metabolism to promote escape mechanisms. Anoikis, a specialized form of programmed cell death, is evaded by LUAD cells during tumor progression and metastasis through upregulation of anti-apoptotic proteins. Investigating the impact of hypoxia-anoikis-related genes on prognosis and therapy prediction in LUAD is essential. Gene expression and clinical data from 489 LUAD patients and 49 normal tissues in The Cancer Genome Atlas (TCGA) dataset were used as the training set, while GSE72094, GSE31210, and GSE30219 datasets were used for validation. Weighted Gene Co-Expression Network Analysis (WGCNA) identified genes associated with hypoxia and anoikis. Machine learning models were evaluated using the C-index. Kaplan-Meier survival analysis, immune cell infiltration, tumor mutational burden (TMB), and sensitivity to therapy were assessed based on risk scores. A total of 21 hypoxia-anoikis-related prognostic genes were identified. The Random Survival Forest (RSF) model had the highest C-index. High-risk patients had significantly lower survival rates. Immune analysis showed higher immune infiltration in the low-risk group, with lower immune escape potential in these patients. Risk scores were correlated with sensitivity to targeted therapy and chemotherapy. MCF2 was identified as a key prognostic gene, and its knockdown inhibited LUAD cell proliferation and metastasis. These 21 genes offer insights into LUAD prognosis and therapy response, guiding personalized treatment strategies for LUAD patients.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 8","pages":"3762-3780"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063119","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}