Carcinogenesis最新文献

From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression. 从前驱体到癌症：胰腺上皮内瘤发展的内在和外在途径解码。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-08 DOI: 10.1093/carcin/bgae064

Sarah Graham, Mariia Dmitrieva, Debora Barbosa Vendramini-Costa, Ralph Francescone, Maria A Trujillo, Edna Cukierman, Laura D Wood

{"title":"From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression.","authors":"Sarah Graham, Mariia Dmitrieva, Debora Barbosa Vendramini-Costa, Ralph Francescone, Maria A Trujillo, Edna Cukierman, Laura D Wood","doi":"10.1093/carcin/bgae064","DOIUrl":"https://doi.org/10.1093/carcin/bgae064","url":null,"abstract":"This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer. 外源性或原位疫苗接种引发胰腺癌临床反应。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-08 DOI: 10.1093/carcin/bgae065

Gregory L Beatty, Elizabeth M Jaffee

{"title":"Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer.","authors":"Gregory L Beatty, Elizabeth M Jaffee","doi":"10.1093/carcin/bgae065","DOIUrl":"https://doi.org/10.1093/carcin/bgae065","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Redefining pancreatic cancer management with tumor-agnostic precision medicine. 用肿瘤诊断精准医学重新定义胰腺癌治疗。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-08 DOI: 10.1093/carcin/bgae066

Neha K Reddy, Vivek Subbiah

{"title":"Redefining pancreatic cancer management with tumor-agnostic precision medicine.","authors":"Neha K Reddy, Vivek Subbiah","doi":"10.1093/carcin/bgae066","DOIUrl":"https://doi.org/10.1093/carcin/bgae066","url":null,"abstract":"Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The evolving role for surgery in pancreatic cancer. 外科手术在胰腺癌中不断演变的角色。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-08 DOI: 10.1093/carcin/bgae062

David Tuveson, Peter Allen

引用次数: 0

CAFomics: convergence to translation for precision stroma approaches. CAFomics：精准基质方法的转化。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-08 DOI: 10.1093/carcin/bgae063

Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh

{"title":"CAFomics: convergence to translation for precision stroma approaches.","authors":"Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh","doi":"10.1093/carcin/bgae063","DOIUrl":"https://doi.org/10.1093/carcin/bgae063","url":null,"abstract":"A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The high stromal density is associated with higher intratumor pressures which, until the last decade, was largely assumed to be tumor protective, confirmed by early studies demonstrating that altering the stroma was effective in genetically engineered models of PDAC. However, clinical trials using these approaches have been disappointing. There is increasing recognition that stroma heterogeneity is much greater than initially thought with an explosion of investigation into cancer-associated fibroblast (CAF) subpopulations led by experimental and single-cell transcriptomic studies. This review summarizes and attempts to harmonize the current transcriptomic data of CAF subpopulations. Understanding the heterogeneity of CAFs, the matrix, and other tumor microenvironment features will be critical to developing effective therapeutic approaches. Identifying model systems that best recapitulate the clinical behavior and treatment response of human PDAC will be important. Examining subpopulations as defined by clinical outcome will remain a critical step in defining clinically impactful CAF subtypes in larger clinical cohorts. The future of precision oncology in PDAC will depend on the integration of precision tumor epithelial and precision stroma approaches.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice partly through a FAK-dependent mechanism. 抑制磷脂酶 D1 可部分通过 FAK 依赖性机制减少小鼠胰腺癌的发生。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-02 DOI: 10.1093/carcin/bgae071

Hala A Addassi, Irena Krga, Fernando Villarreal, Joseph F LaComb, Michael A Frohman, Karen Matsukuma, Gerardo G Mackenzie

{"title":"Inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice partly through a FAK-dependent mechanism.","authors":"Hala A Addassi, Irena Krga, Fernando Villarreal, Joseph F LaComb, Michael A Frohman, Karen Matsukuma, Gerardo G Mackenzie","doi":"10.1093/carcin/bgae071","DOIUrl":"https://doi.org/10.1093/carcin/bgae071","url":null,"abstract":"Phospholipase D (PLD) plays a critical role in cancer progression. However, its role in pancreatic cancer remains unclear. Thus, we evaluated the role of PLD1, one of two classical isoforms of PLD, in pancreatic carcinogenesis in vivo. The role of PLD1 in tumor growth was evaluated by subcutaneously transplanting human MIA PaCa-2 cells expressing endogenous PLD1 levels (Ctr KD cells) or cells in which PLD1 was knocked down (Pld1 KD cells) into immunodeficient mice. Twenty days post-implantation, tumors that arose from Pld1-KD cells were significantly smaller, compared to controls (Ctr KD). Then, we assessed the role of PLD1 in the tumor microenvironment, by subcutaneously implanting mouse LSL-KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) cells into wild-type (WT) or PLD1 knockout (Pld1-/-) mice. Compared to WT, tumor growth was attenuated in Pld1-/- mice by 39%, whereas treatment of Pld1-/- mice with gemcitabine reduced tumor growth by 79%. When PLD1 was ablated in LSL-KrasG12D;Ptf1Cre/+ (KC) mice, no reduction in acinar cell loss was observed, compared to KC mice. Finally, treatment of KC mice with a small molecule inhibitor of PLD1 and PLD2 (FIPI) significantly reduced acinar cell loss and cell proliferation, compared to vehicle-treated mice. Mechanistically, the effect of PLD on tumor growth is mediated, partly, by the FAK pathway. In conclusion, while PLD1 is a critical regulator of pancreatic xenograft and allograft growth, playing an important role at the tumor and at the microenvironment levels, inhibition of PLD1 and PLD2 are necessary to reduce pancreatic carcinogenesis in KC mice, and might represent a novel therapeutic target.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Colorectal cancer cells with high metastatic potential drive metastasis by transmitting exosomal miR-20a-3p through modulating NF1/MAPK pathway. 具有高转移潜能的结直肠癌细胞通过调节 NF1/MAPK 通路传递外泌体 miR-20a-3p 推动转移。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae036

Yahang Liang, Junyu Li, Tao Li, Mingming Li, Hualin Liao, Yang Liu, Yao Yao, Lingling Yang, Xiong Lei

{"title":"Colorectal cancer cells with high metastatic potential drive metastasis by transmitting exosomal miR-20a-3p through modulating NF1/MAPK pathway.","authors":"Yahang Liang, Junyu Li, Tao Li, Mingming Li, Hualin Liao, Yang Liu, Yao Yao, Lingling Yang, Xiong Lei","doi":"10.1093/carcin/bgae036","DOIUrl":"10.1093/carcin/bgae036","url":null,"abstract":"Cancer cells exhibit heterogeneous metastatic potential, and high metastatic (HM) subclones can enhance the metastatic potential of low metastatic subclones by transmitting some factors. Exosomal miRNAs play a pivotal role in the crosstalk of heterogeneous metastatic subclones. This study discovered that miR-20a-3p was upregulated in colorectal adenocarcinoma (CRA), correlated with metastasis, and potentially served as a prognostic indicator for CRA. miR-20a-3p could promote the proliferation, migration, and invasion of CRA cells. Interestingly, HM CRA cells could promote malignant phenotypes of low metastatic CRA cells by transmitting exosomal miR-20a-3p. Mechanically, miR-20a-3p could inhibit neurofibromin 1(NF1), thereby activate the rat sarcoma viral oncogene (RAS)-mediated mitogen-activated protein kinases (MAPK) signaling pathway to drive the metastasis of CRA. In summary, our study provided evidence that colorectal cancer cells with HM potential drive metastasis by transmitting exosomal miR-20a-3p through modulating the NF1/MAPK pathway.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer. 脱氢阿糖胞苷胺通过影响胃癌核苷酸代谢发挥抗肿瘤作用

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae037

Jingsong Ma, Jiabao Zhao, Zhengxin Wu, Jinshui Tan, Meijuan Xu, Wenjie Ye, Mengya Zhong, Yubo Xiong, Guangchao Pan, Huiwen Zhou, Shengyi Zhou, Xuehui Hong

{"title":"Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.","authors":"Jingsong Ma, Jiabao Zhao, Zhengxin Wu, Jinshui Tan, Meijuan Xu, Wenjie Ye, Mengya Zhong, Yubo Xiong, Guangchao Pan, Huiwen Zhou, Shengyi Zhou, Xuehui Hong","doi":"10.1093/carcin/bgae037","DOIUrl":"10.1093/carcin/bgae037","url":null,"abstract":"Nucleotide metabolism is the ultimate and most critical link in the self-replication process of tumors, including gastric cancer (GC). However, in clinical treatment, classic antitumor drugs such as 5-fluorouracil (5-FU) are mostly metabolic analogs of purines or pyrimidines, which lack specificity for tumor cells and therefore have significant side effects. It is unclear whether there are other drugs that can target nucleotide metabolism, except for nucleic acid analogs. Here, we found that a natural compound, dehydroabietylamine (DHAA), significantly reduced the viability and proliferation of GC cells and organoids. DHAA disrupts the purine and pyrimidine metabolism of GC cells, causing DNA damage and further inducing apoptosis. DHAA treatment decreased transcription and protein levels of key enzymes involved in the nucleotide metabolism pathway, with significant reductions in the expression of pyrimidine metabolism key enzymes CAD, DHODH, and purine metabolism key enzymes PAICS. We also found that DHAA directly binds to and reduces the expression of Forkhead box K2 (FOXK2), a common transcription factor for these metabolic enzymes. Ultimately, DHAA was shown to delay tumorigenesis in K19-Wnt1/C2mE transgenic mice model and reduce levels of CAD, DHODH, and PAICS in vivo. We demonstrate that DHAA exerts an anticancer effect on GC by targeting transcription factor FOXK2, reducing transcription of key genes for nucleotide metabolism and impairing nucleotide biosynthesis, thus DHAA is a promising candidate for GC therapy.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310123","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}

引用次数: 0

Allura Red AC is a xenobiotic. Is it also a carcinogen? Allura Red AC 是一种异生物。它也是一种致癌物质吗？

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae057

Lorne J Hofseth, James R Hebert, Elizabeth Angela Murphy, Erica Trauner, Athul Vikas, Quinn Harris, Alexander A Chumanevich

{"title":"Allura Red AC is a xenobiotic. Is it also a carcinogen?","authors":"Lorne J Hofseth, James R Hebert, Elizabeth Angela Murphy, Erica Trauner, Athul Vikas, Quinn Harris, Alexander A Chumanevich","doi":"10.1093/carcin/bgae057","DOIUrl":"10.1093/carcin/bgae057","url":null,"abstract":"Merriam-Webster and Oxford define a xenobiotic as any substance foreign to living systems. Allura Red AC (a.k.a., E129; FD&C Red No. 40), a synthetic food dye extensively used in manufacturing ultra-processed foods and therefore highly prevalent in our food supply, falls under this category. The surge in synthetic food dye consumption during the 70s and 80s was followed by an epidemic of metabolic diseases and the emergence of early-onset colorectal cancer in the 1990s. This temporal association raises significant concerns, particularly given the widespread inclusion of synthetic food dyes in ultra-processed products, notably those marketed toward children. Given its interactions with key contributors to colorectal carcinogenesis such as inflammatory mediators, the microbiome, and DNA damage, there is growing interest in understanding Allura Red AC's potential impact on colon health as a putative carcinogen. This review discusses the history of Allura Red AC, current research on its effects on the colon and rectum, potential mechanisms underlying its impact on colon health, and provides future considerations. Indeed, although no governing agencies classify Allura Red AC as a carcinogen, its interaction with key guardians of carcinogenesis makes it suspect and worthy of further molecular investigation. The goal of this review is to inspire research into the impact of synthetic food dyes on colon health.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916164","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}

引用次数: 0

CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma. CDK12 是转移性骨肉瘤转录周期和 DNA 损伤反应的一个很有前景的治疗靶点。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae051

Zihao Li, Xiaoyang Li, Nicole A Seebacher, Xu Liu, Wence Wu, Shengji Yu, Francis J Hornicek, Changzhi Huang, Zhenfeng Duan

{"title":"CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma.","authors":"Zihao Li, Xiaoyang Li, Nicole A Seebacher, Xu Liu, Wence Wu, Shengji Yu, Francis J Hornicek, Changzhi Huang, Zhenfeng Duan","doi":"10.1093/carcin/bgae051","DOIUrl":"10.1093/carcin/bgae051","url":null,"abstract":"Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents, and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12 and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. The underlying mechanism revealed that knockdown of CDK12 expression with small interfering RNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0