Carcinogenesis最新文献

Most tissues are continuously renovated through the division of stem cells and the death of old or damaged cells, which is known as the cell turnover rate (CTOR). Despite being in a steady state, tissues have different population dynamics thus producing diverse clonality levels. Here, we propose and test that cell population dynamics can be a cancer driver. We employed the evolutionary software esiCancer to show that CTOR, within a range comparable to what is observed in human tissues, can amplify the risk of a mutation due to ancestral selection (ANSEL). In a high CTOR tissue, a mutated ancestral cell is likely to be selected and persist over generations, which leads to a scenario of elevated ANSEL profile, characterized by few niches of large clones, which does not occur in low CTOR. We found that CTOR is significantly associated with the risk of developing cancer, even when correcting for mutation load, indicating that population dynamics per se is a cancer driver. This concept is central to understanding cancer risk and for the design of new therapeutic interventions that minimizes the contribution of ANSEL in cancer growth.

Acute lymphoblastic leukemia (ALL) is a heterogeneous clonal disease originated from B- or T-cell lymphoid precursor cells. ALL is often refractory or relapses after treatment. Novel treatments are anxiously needed in order to achieve a better response and prolonged overall survival in ALL patients. In the present study, we aimed at examining the antitumor effect of niclosamide on ALL. We investigated the effects of niclosamide on the proliferation and apoptosis in vitro, the growth of ALL cells in xenografted NOD-Prkdcem26Cd52 il2rgem26Cd22 /Nju (NCG) mice. The results showed that niclosamide treatment potently inhibited the growth of ALL cells and induced apoptosis via elevating the levels of reactive oxygen species and activating TP53. These findings suggest that niclosamide may be a promisingly potential agent for ALL therapy.

In this study, we evaluated the effects of vitamin E δ-tocotrienol (DT3) and aspirin on Wnt signaling in human colon cancer stem cells (CCSCs) and in the prevention of adenoma formation in APCmin/+ mice. We found that knockdown of the adenomatous polyposis coli (APC) gene led to subsequent activation of Wnt signaling in colon epithelial cells (NCM460-APCsiRNA) and induction of β-catenin and its downstream target proteins c-MYC, cyclin D1, and survivin. When aspirin and DT3 were combined, cell growth and survival were inhibited and apoptosis was induced in colon epithelial cells and CCSCs. However, DT3 and/or aspirin had little or no effect on the control of normal colon epithelial cells (NCM460-NCsiRNA). The induction of apoptosis was directly related to the activation of caspase 8 and cleavage of BH3-interacting-domain (BID) to truncated BID. In addition, DT3- and/or aspirin-induced apoptosis was associated with cleaved Poly (ADP-ribose) polymerase (PARP), elevated levels of cytosolic cytochrome c and BAX, and depletion of antiapoptotic protein BCl-2 in CCSCs. The combination of aspirin and DT3 inhibited the self-renewal capacity, Wnt/β-catenin receptor activity, and expression of β-catenin and its downstream targets c-MYC, cyclin D1, and survivin in CCSCs. We also found that treatment with DT3 alone or combined with aspirin significantly inhibited intestinal adenoma formation and Wnt/β-catenin signaling and induced apoptosis, compared with vehicle, in APCmin/+ mice. Our study demonstrated a rationale for further investigation of the combination of DT3 and aspirin for colorectal cancer prevention and therapy.

STIP1 homology and U-box protein 1 (STUB1), a crucial member of the RING family E3 ubiquitin ligase, serve dual roles as an oncogene and a tumor suppressor in various human cancers. However, the role and mechanism of STUB1 in clear cell renal cell carcinoma (ccRCC) remain poorly defined. Here, we identified YTHDF1 as a novel STUB1 interaction partner using affinity purification mass spectrometry. Furthermore, we revealed that STUB1 promotes the ubiquitination and degradation of YTHDF1. Consequently, STUB1 depletion leads to YTHDF1 upregulation in renal cancer cells. Functionally, STUB1 depletion promoted migration and invasion of ccRCC cells in a YTHDF1-dependent manner. Additionally, the depletion of STUB1 also increased the tumorigenic potential of ccRCC in a xenograft model. Importantly, STUB1 expression is downregulated in ccRCC tissues, and its low expression level correlates with advanced tumor stage and poor overall survival in ccRCC patients. Taken together, these findings reveal that STUB1 inhibits the tumorigenicity of ccRCC by regulating YTHDF1 stability.

Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g. using EIPA or EHoP-016) or genetic interventions (e.g. RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia-inducible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

Testicular tumors are the most common malignancy of young men and tumors affecting the testis are caused by somatic mutations in germ or germ-like cells. The PI3K pathway is constitutively activated in about one third of testicular cancers. To investigate the role of the PI3K pathway in transforming stem-like cells in the testis, we investigated tumors derived from mice with post-natal, constitutive activation of PI3K signaling and homozygous deletion of tumor suppressor Pten, targeted to nestin expressing cells. Mice developed aggressive tumors, exhibiting heterogeneous histopathology and hemorrhaging. The tumors resemble the rare testis tumor type, testicular sex cord-stromal Leydig cell tumors. Single cell resolution spatial tissue analysis demonstrated that T-cells are the dominant tumor infiltrating immune cell type, with very few infiltrating macrophages observed in the tumor tissue, with CD8+ T-cells predominating. Further analysis showed that immune cells preferentially localize to or accumulate within stromal regions.

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.