Molecular Carcinogenesis最新文献

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.

Serine palmitoyltransferase long chain-1 (SPTLC1) is a key enzyme in ceramide synthesis, previously identified as a suppressor of tumorigenesis in clear cell renal carcinoma (ccRCC). Although elevated levels of very long-chain ceramides are associated with the canonical multidrug resistance in ccRCC, the specific role of SPTLC1 in modulating the sensitivity of ccRCC to sunitinib remains unclear. In this study, we found that SPTLC1 overexpression could enhance the sensitivities of 786-O and OSRC-2 cells to sunitinib via downregulating CerS2 expression and long-chain ceramide levels. In contrast, SPTLC1 upregulated CerS2 expression and long-chain ceramide levels in A498 cells, yet without a significant impact on its sensitivity to sunitinib. In addition, overexpression of CerS2 significantly attenuated SPTLC1-enhanced sensitivities of 786-O and OSRC-2 cells to sunitinib, whereas CerS2 knockdown obviously enhanced the sensitivity of A498 cells to sunitinib. Moreover, androgen receptor (AR) expression was significantly decreased in SPTLC1-overexpressed 786-O cells and forced AR expression could obviously attenuate the downregulation of CerS2 expression induced by SPTLC1 in 786-O cells, whereas opposite results were observed in A498 cells, suggesting that the contradictory effects of SPTLC1 on CerS2 expression were modulated by AR. Taken together, our results demonstrated that the contradictory effects of SPTLC1 on clear cell renal carcinoma sensitivity to sunitinib were caused by AR-mediated CerS2 expression, thus revealing a novel role and mechanism of SPTLC1 in the regulation of ccRCC sensitivity to sunitinib.

Hepatocellular carcinoma (HCC), whose complex etiology involves a genetic component, is a global public health burden. Tumor necrosis factor superfamily member 15 (TNFSF15) is a T lymphocyte-costimulatory cytokine known to modulate angiogenesis and inflammation, implicating its potential role in cancer development. In this study, we attempted to explore the influence of TNFSF15 gene variations on the risk for HCC. In total, 408 HCC patients and 1190 noncancer controls were enrolled, and allelic distributions of TNFSF15 gene (rs3810936, rs6478108, and rs6478109) were analyzed using a TaqMan allelic discrimination assay. After adjustment for the putative confounding factors, none of these three SNPs was associated with the development of HCC. While assessing the clinicopathological parameters, we demonstrated that patients carrying at least one minor allele of rs6478108 (T) or rs6478109 (G) were less prone to develop distant metastasis (rs6478108, TC + TT vs. CC, OR, 0.414; 95% CI, 0.185-0.924, p = 0.027) (rs6478109, GA + GG vs. AA, OR, 0.397; 95% CI, 0.178-0.888; p = 0.021) as compared with patients who are homozygous for the major allele. In addition, preliminary exploration of public datasets exhibited that rs6478108 and rs6478109 affected TNFSF15 gene expression to various degrees in the liver tissues and whole blood samples. Moreover, gene silencing experiments revealed that elevated TNFSF15 levels are essential for promoting cell migration in HCC. Our results indicate gender-specific association of TNFSF15 gene polymorphisms with the metastatic potential of HCC.

Ferroptosis, an iron-dependent form of programmed cell death, is emerging as a novel approach to tackling cancer. Cancer cells require large amounts of iron for their rapid growth, making them intrinsically vulnerable to ferroptosis. However, cancer cells have developed several important antioxidant pathways to counteract ferroptosis. One of these key pathways is the FSP1/CoQH2 pathway. In this study, we reveal a new regulatory mechanism of FSP1 involving the Pregnane X Receptor (PXR). Activation of PXR by rifaximin and rifampicin suppresses ferroptosis in a variety of cancer cells from different origins. The protective effect of rifaximin and rifampicin is lost in PXR knockout cells or in the presence of PXR inhibitor, validating the role of PXR in mediating the effects of these drugs. Additionally, rifaximin and rifampicin decrease lipid peroxidation and ferrous iron accumulation during ferroptosis induction, effects that are reversed in PXR knockout cells. Mechanistically, rifaximin and rifampicin induce the expression of FSP1 in a PXR-dependent manner, as they fail to induce FSP1 in PXR knockout cells. Furthermore, the ferroptosis protection effect of rifaximin and rifampicin is significantly compromised in FSP1 knockout cells or in the presence of the FSP1 inhibitor iFSP1. Importantly, we demonstrated that the PXR inhibitor pimecrolimus showed synergy with ferroptosis inducer sulfasalazine to repress tumor growth in vivo. Together, these findings provide evidence supporting an anti-ferroptosis role of PXR through the upregulation of FSP1 expression.

Bladder cancer (BC) represents the second most prevalent malignant tumor within the urinary system. Its high rates of recurrence and metastasis contribute to an unfavorable prognosis. The myeloma overexpressed gene (MYEOV) has been associated with the progression of various cancers. However, the specific role and underlying mechanisms of MYEOV in BC progression remain to be elucidated. Our research demonstrates that MYEOV is significantly upregulated in BC and correlates with poor clinical outcomes. Reducing or overexpressing MYEOV can inhibit or promote the proliferation and invasive ability of BC. Mechanistically, MYEOV activates the TGF-β-H3K4me3 signaling pathway to directly modulate MMP9 promoter activity through epigenetic modifications, thereby enhancing MMP9 expression. Notably, the effects of MYEOV knockdown or overexpression on BC proliferation and invasion can be counteracted by restoring MMP9 expression. Furthermore, NSUN2 modulates the stability of MYEOV mRNA via m5C methylation, leading to its increased expression in BC. Collectively, our findings elucidate the role of MYEOV in facilitating BC progression through the regulation of MMP9 in vitro. In conclusion, our findings identified that MYEOV is a novel target in the development of bladder cancer and offer new insights into potential therapeutic strategies.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and fatal cancers in India. Silibinin, a naturally occurring small molecule from milk thistle (Silybum marianum), is gaining attention as a potent anticancer agent against various cancers; however, its impact on HNSCC and the associated molecular mechanisms are largely unknown. We checked the effect of silibinin on proliferation, cell viability, and DNA damage in HNSCC cells, and employed immunoblotting to detect the underlined molecular mechanism. Also, we validated silibinin's anticancer efficacy and associated molecular changes in the xenograft mouse model. Silibinin inhibited cell proliferation and viability in HNSCC cells, and enhanced G1-S phase arrest by increasing p53 expression and inhibiting p27^Kip1, p21^Cip1, Cyclin D1-CDK4/6, and Cyclin E-CDK2 complexes. Silibinin-induced DNA damage and apoptosis in HNSCC cells were evidenced by comet assay, expression of p-H2AX, Bax, Bcl-2, and cleavage of caspase 3 and PARP proteins. Moreover, silibinin also impaired DNA repair pathways, ATM-Chk2, ATR-Chk1, DNA-PK, Ku70/80 and Rad51, and activated JNK contributing to DNA damage. The strong inhibition of EGFR-mediated Erk1/2, AKT and STAT3 signaling by silibinin was identified. Silibinin augmented PD98059 and LY294002-induced cell death and inhibition of pSTAT3. Silibinin inhibited Cal33 tumor growth in athymic mice model without any adverse effects. Our study revealed anticancer efficacy of silibinin in suppressing cell viability and proliferation, promoting DNA damage, apoptosis and cell cycle arrest in HNSCC. Further, oral silibinin inhibited Cal33 tumor xenograft growth. Hence, silibinin could have promising therapeutic efficacy for HNSCC.