Molecular Carcinogenesis最新文献

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy, severely compromising treatment efficacy and the patients' quality of life, yet effective prevention or treatment strategies remain elusive. Folic acid (FA), a water-soluble vitamin, plays critical roles in DNA synthesis/repair, cell cycle regulation, epigenetic regulation via methylation, oxidative stress response, and embryonic development. However, its radioprotective role has not been systematically elucidated. This study aimed to investigate its effects and molecular mechanisms during RILI. The RILI murine model showed that folic acid supplementation significantly alleviated radiation-induced lung tissue damage, body weight loss, and inflammatory cell infiltration. Meanwhile, folic acid mitigated radiation-induced DNA damage and cellular senescence in lung tissues and lung epithelial cell lines. RNA sequencing identified a 29-gene SASP signature (including CCL5, CXCL2, CXCL10), which was significantly suppressed by folic acid in irradiated lungs. Moreover, folic acid inhibited SASP production by suppressing the phosphorylation of P38 MAPK/NF-κB signaling pathway. By integrating in vivo and in vitro models, we revealed that folic acid exerts its radioprotective effects by reducing cellular senescence and the production of SASP. Taken together, these findings indicated that folic acid is potentially a novel therapeutic strategy for RILI.

GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine in the tissue microenvironment activates GCN2 and alters stromal cell metabolism to support tumor cell survival and drive myeloid immunosuppressive function. To study the effect of elevated polyamine metabolism on fibroblast activation, we used the K6/ODC transgenic model of carcinogen-initiated, polyamine-promoted skin carcinogenesis. GCN2 loss significantly delayed tumor development and decreased tumor number and tumor burden in K6/ODC; GCN2^-/- mice compared that in K6/ODC mice. Underlying dermal fibroblasts from nontumor bearing K6/ODC mice express elevated levels of genes associated with GCN2 activation and fibroblast activation. Expression of these genes was not elevated in K6/ODC; GCN2^-/- dermis. In addition, K6/ODC mice have significantly more myeloid derived suppressor cells (MDSC) compared to normal littermates, and MDSCs were decreased in K6/ODC mice deficient in GCN2. Dermal fibroblasts cultured from K6/ODC transgenic mouse skin secrete increased levels of protumorigenic factors including senescence associated secretory phenotype (SASP) factors that stimulate invasiveness of stem-like epidermal tumorspheres as well as the polarization of M2-like macrophages. Using K6/ODC; p16-3MR mice in which senescent fibroblasts can be eliminated with ganciclovir treatment, carcinogen-initiated tumor development was greatly inhibited when senescent fibroblasts were eliminated in K6/ODC; p16-3MR mice. Our studies suggest a new paradigm in which cellular stress responses resulting from increased polyamine biosynthesis accelerate fibroblast activation and a senescence phenotype to create a protumorigenic microenvironment.

Breast cancer is the most common malignancy that threaten women's health seriously. Many studies have shown that long noncoding RNAs can play significant role in the tumorigenesis of breast cancer. By analyzing the TCGA breast cancer genome data and transcriptome data, we found that copy number amplification drives the activation of long noncoding RNA MNX1-AS in breast cancer and indicates poor prognosis. Functionally, MNX1-AS1 could regulate pathogenesis of breast cancer in vitro and in vivo. Mechanistically, MNX1-AS1 could bind IGF2BP1, which increased the interaction of IGF2BP1 with MET mRNA to promote its stability, thus promoting tumorigenesis of breast cancer. Moreover, combination of MNX1-AS1 inhibition and MET small molecule inhibitor (PHA-665752, PHA) exhibited better antitumor efficacy in xenograft model, suggesting the therapeutic potential. Overall, our findings indicated that MNX1-AS1/MET regulatory axis may serve as a potential therapeutic target in breast cancer.

This study aimed to study the mechanism by which m6A methyltransferase, KIAA1429, affect pancreatic adenocarcinoma (PAAD) cell malignant behaviors in relation to N6-methyladenosine (m6A) modification. RT-qPCR, Western blot, immunohistochemistry (IHC), and m6A RNA immunoprecipitation (Me-RIP) assays were performed on PAAD tumor and adjacent non-tumor tissues (n = 39) to detect KIAA1429, AKT2 mRNA and protein levels, as well as overall tissue RNA m6A methylation levels. Tumor cells were transfected with siRNA targeting KIAA1429 (si-KIAA1429) or plasmids overexpressing AKT2 (oe-AKT2). Cell activities were assessed, followed by assessment of autophagic flux using the mRFP-GFP-LC3 reporter. In PAAD tissues and cell lines, KIAA1429 was substantially expressed. In PAAD patients, this expression was linked to a considerably lower overall and disease-specific survival rate. KIAA1429 knockdown inhibited PAAD cell malignant behaviors and promoted autophagy. Mechanistically, KIAA1429 mediated AKT2 m6A modification to enhance AKT2 mRNA stability and upregulate AKT2 expression, partially reversing the mediating effects of KIAA1429 knockdown on PAAD cell malignant behaviors and autophagy. KIAA1429 knockdown also inhibited PAAD tumor growth in vivo. KIAA1429 promotes PAAD cell malignant behaviors while inhibiting autophagy activity by mediating AKT2 m6A modification and enhancing AKT2 expression.

Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Temozolomide (TMZ) stands for the first-line chemotherapeutic agent against GBM. TMZ resistance is an important factor contributing to the poor prognosis of GBM, but the underlying molecular mechanisms are unclear. Previous studies have suggested that KIF4A may be an indicator of poor prognosis in glioma patients, but the association of KIF4A with TMZ resistance has never been investigated. The detection of ferroptosis levels in GBM cells was accomplished through the utilization of ROS, MDA, JC-1, and Western blot analysis. The assessment of TMZ resistance was performed through the implementation of CCK8, cell cloning, and cell cycle analysis. The identification of downstream targets of KIF4A was facilitated by protein profiling and immunofluorescence. KIF4A inhibits ferroptosis in GBM cells through the CHMP4B/GPX4 axis and promotes TMZ resistance. Knockdown of KIF4A or CHMP4B sensitized GBM cells to chemotherapy. In addition, KIF4A induced epithelial-mesenchymal transition in GBM cells, which synergistically promoted TMZ resistance.The present study elucidates a novel mechanism of TMZ resistance in glioblastoma through the CHMP4B/GPX4 axis. Based on these findings, targeting KIF4A may offer a potential new strategy against GBM.

Circular RNAs (circRNAs) are covalently closed RNA molecules that play critical roles in tumorigenesis and cancer progression, including colorectal cancer (CRC). However, the clinical significance, biological functions, and molecular mechanisms of many novel circRNAs in CRC remain poorly understood. In this study, we identified a novel circRNA, hsa_circ_0003759 (designated circLPP), which was significantly upregulated in CRC tissues. High circLPP expression correlated with malignant progression and poor prognosis in CRC patients. Functional experiments demonstrated that circLPP promoted CRC proliferation and migration both in vitro and in vivo. Mechanistically, circLPP upregulated Wnt3a expression and activated the Wnt/β-catenin signaling pathway by sponging miR-665. Our findings revealed that circLPP driven CRC progression by modulating the Wnt/β-catenin pathway, highlighting its potential as a therapeutic target for CRC.

Epithelial-mesenchymal transition (EMT) has been shown to facilitate lung adenocarcinoma (LUAD) progress, and KLF13 inhibits tumor progression in various cancers. We intended to explore the mechanisms of KLF13 on EMT in LUAD. The biological functions (including cell viability, invasion, migration, and EMT) were checked using CCK-8, Transwell, and wound healing. The KLF13 and EMT markers levels were detected by immunohistochemistry. Interaction between KLF13 and TROAP promoter was probed by ChIP and dual luciferase reporter gene assay. The association between FBXW5 and KLF13 was verified by CoIP. RT-qPCR or Western blot was employed to check the expressions of FBXW5, KLF13, TROAP, and EMT markers. A xenograft tumor model was constructed to determine the growth of LUAD cells. KLF13 was lowly expressed in LUAD tissues and cells. KLF13 inhibited the invasion, migration, and EMT of LUAD cells. KLF13 suppressed TROAP transcription, and overexpression of TROAP reversed the inhibitory effect of KLF13 on the biological functions of LUAD cells. FBXW5 promoted KLF13 ubiquitinated degradation, and the knockdown of FBXW5 promoted KLF13 to inhibit LUAD cell progression. FBXW5 promoted KLF13 ubiquitinated degradation, which downregulated KLF13 to increase TROAP transcription, thereby facilitating EMT in LUAD.

Glycosylation abnormalities are critical in the progression of various cancers. However, their role in the onset and prognosis of multiple myeloma (MM) remains underexplored. This study aims to identify glycosyltransferase (GT)-related biomarkers and investigate their underlying mechanisms in MM. GT-related genes were extracted from the MMRF-CoMMpass and GSE57317 data sets. Potential biomarkers were identified using Cox regression and Lasso analyses. A glycosyltransferase-related prognostic model (GTPM) was developed by evaluating 113 machine learning algorithm combinations. The expression of B4GALT3, a key gene identified through this model, was analyzed in MM bone marrow samples using immunohistochemistry, quantitative PCR, and Western blot. Functional roles of B4GALT3 in MM cell behavior were assessed through knockdown experiments, and its mechanism of action was investigated. The GTPM stratified MM patients into high- and low-risk groups, with significantly better survival in the low-risk group (HR = 55.94, 95% CI = 40.48-77.31, p < 0.001). The model achieved AUC values of 0.98 and 0.99 for 1- and 3-year overall survival, outperforming existing gene signatures (including EMC92, UAMS70, and UAMS17). B4GALT3 expression was significantly elevated in advanced MM stages (p < 0.001) and correlated with poorer survival. Knockdown of B4GALT3 reduced MM cell proliferation, invasion, and increased apoptosis. Mechanistic analyses revealed that B4GALT3 modulates MM cell behavior via the Wnt/β-catenin/GRP78 pathway, primarily by regulating endoplasmic reticulum (ER) stress. This study developed a novel GTPM for predicting survival in MM and identified B4GALT3 as a key gene influencing disease progression. Experimental evidence highlights B4GALT3's role in modulating ER stress and Wnt/β-catenin pathways, positioning it as a potential prognostic biomarker and therapeutic target in MM.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma characterized by high rates of relapse and limited responsiveness to standard chemotherapy. Selinxor, a selective inhibitor of XPO1, exhibited antitumor activity in various cancers. However, clinical trial results revealed that selinexor monotherapy exhibited unsatisfactory efficacy in DLBCL. Our study indicated that XPO1 expression was increased in DLBCL and was correlated with poor outcomes of DLBCL patients. Comprehensive proteomic and transcriptomics analysis showed that selinexor has significant impacts on various biological processes in DLBCL. Furthermore, we explored combination strategies involving selinexor to enhance DLBCL treatment. We examined the combined effects of selinexor with decitabine (DAC) and lenalidomide (LEN), and found that selinexor exhibited a synergistic effect with DAC against DLBCL. Further analysis revealed that DAC exerted a synergistic antitumor effect with selinexor by reversing the DNMT1 expression and DNA methylation alterations induced by selinexor. Overall, these findings provided valuable insights into the global impact of selinexor on DLBCL. The combination therapy of selinexor and DAC emerges as a highly promising strategy for effectively treating DLBCL, holding great potential for clinical application.

Despite notable advancements in therapeutic modalities, many patients with colorectal cancer (CRC) exhibit inadequate response to regorafenib, largely due to the propensity for drug resistance. Deeper insights into the mechanism of CRC sensitivity to regorafenib therapy are urgently required. The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is closely associated with a variety of malignancies. Therefore, this study investigated the role of BCL-2 in promoting regorafenib resistance in colorectal cancer. Venetoclax, a BCL-2 antagonist, potentiates the antitumor activity of regorafenib. The combination of regorafenib and Venetoclax inhibited the proliferation and promoted apoptosis of CRC cells and human umbilical vein endothelial cells in vitro by inhibiting tumor angiogenesis, promoting normalization of tumor blood vessels, and promoting immune cell infiltration and the release of immune cytotoxic factors. Although Venetoclax is primarily used clinically to treat hematological tumors, it has not yet been used to treat CRC. These findings provide new insights for the clinical treatment of CRC.