Molecular Carcinogenesis最新文献

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.

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.

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.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the deadliest liver disease. It is imperative to understand the underlying molecular mechanisms involved in the development of HCC. Monocarboxylate transporter-1 (MCT1) is a proton-coupled protein that facilitates the bidirectional transport of monocarboxylates, such as lactate and pyruvate, across the plasma membrane to maintain the cellular metabolism and energy supply. MCT1 was found to be upregulated in human HCC specimens, and its inhibition reduced xenograft tumor growth. However, the role of MCT1 in HCC remains to be further investigated using immune-competent in vivo models. To better understand the role of MCT1 in HCC, we established liver-specific MCT1 knockout mice. We found that deletion of MCT1 in liver cells did not affect morphology, proliferation, or apoptosis. DEN/CCl4 model, where a single injection of DEN is followed by repeated injections of CCl4, was used to induce HCC in mice. Intriguingly, we found that liver-specific knockout of MCT1 was not sufficient to reduce the size or count of DEN/CCl4-induced liver tumors. In addition, we used immunohistochemical staining to evaluate the expression of Ki67, collagen A1, and myeloperoxidase, and we found that MCT1 knockout was not able to hinder the proliferation, fibrosis, and inflammation in the DEN/CCl4-induced HCC tumors. In conclusion, MCT1 is dispensable for HCC development, and its deletion was insufficient to alleviate the phenotypic repercussions of HCC tumors in the DEN/CCl4-induced HCC model.

N⁶-methyladenosine (m⁶A) modification plays a pivotal role in cancer progression, yet its regulatory mechanisms in bladder cancer (BCa) remain poorly understood. This study investigates the functions of two key m⁶A regulators-α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) and KIAA1429-in modulating BCa cell behavior. Expression levels of ALKBH5, KIAA1429, and Sonic Hedgehog (SHH) were examined in BCa tissues and adjacent normal tissues. Functional assays, including methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and RNA stability assessments, were performed in J82 BCa cells to explore the underlying mechanisms. Results revealed that KIAA1429 was significantly upregulated in BCa and promoted cell proliferation, migration, and invasion by enhancing m⁶A modification and stabilizing SHH mRNA, leading to activation of the Hedgehog signaling pathway. In contrast, ALKBH5, which was downregulated in BCa, acted as an m⁶A demethylase that destabilized SHH mRNA and attenuated Hedgehog pathway activity, thereby counteracting the oncogenic effects of KIAA1429. Moreover, overexpression of SHH reversed the inhibitory effects induced by KIAA1429 knockdown, confirming its role as a downstream effector. In conclusion, ALKBH5 and KIAA1429 exert opposing regulatory effects on BCa progression via m⁶A-mediated modulation of SHH expression and Hedgehog signaling. These findings highlight SHH mRNA methylation as a central mechanism in BCa malignancy and identify ALKBH5 and KIAA1429 as potential therapeutic targets.

The transcription factor Myc-associated zinc finger protein (MAZ) is highly expressed in various malignant tumors, and it is known to activate the expression of a large number of proto-oncogenes through transcription. However, the specific molecular mechanism of how MAZ regulates transcriptional repression in hepatocarcinoma remains unclear. To identify the interacting proteins of MAZ, we employed immunoaffinity purification followed by silver-stain mass spectrometry. RNA-seq analysis, RT-PCR, and ChIP assays were utilized to examine the target genes and signaling pathways coregulated by MAZ and HDAC1. Additionally, we conducted EdU incorporation, colony formation, growth curve, TUNEL, transwell, and wound-healing assays, along with immunohistochemical staining, in vivo tumor xenografts, and bioluminescence metastasis assays, to explore the role of the MAZ/HDAC1 complex in tumorigenesis. Our findings revealed that MAZ binds to the transcriptional inhibitory complexes HDAC1, RBBP7, and CUL4B. Transcriptome analysis revealed that MAZ and HDAC1 cooperatively regulate the expression of the CSK gene. Knockdown of either MAZ or HDAC1 activates CSK expression, subsequently inhibiting the MAPK/ERK, STAT3, and PI3K/AKT signaling pathways, thereby suppressing the proliferation and metastasis of hepatocellular carcinoma cells. The proliferation and metastasis phenotypes induced by MAZ knockdown can be rescued by simultaneous knockdown of CSK. In vivo experiments have demonstrated that MAZ knockdown inhibits tumorigenesis and metastasis in mice. Our findings highlight a novel mechanism wherein MAZ plays a transcriptional inhibitory role by recruiting HDAC1 to catalyze histone deacetylation, and the MAZ/HDAC1 complex inhibits CSK expression, thus promoting tumor proliferation and metastasis.

Our previous studies identified the differentially expressed coding and noncoding RNAs during the nigericin-mediated damage by the high-throughput RNA sequencing. However, these reports provided insights into nigericin only through the bioinformatics methods. The anticancer mechanisms of nigericin in pancreatic cancer (PC) have still not been elucidated. In this study, PC cells were exposed to increasing concentrations of nigericin at different time periods, and the corresponding 50% inhibiting concentration (IC50) values were calculated. Then the effects on the biological functions of PC cells were evaluated. Subsequent experiments, including the high-throughput RNA sequencing, qRT-PCR, western blot, TOP/FOP-Flash reporter, Co-Immunoprecipitation (Co-IP) and luciferase reporter assays were employed to reveal the mechanisms of nigericin. In addition, the inhibitory effects of nigericin on PC cells were accessed in the subcutaneous tumor and peritoneal disseminated models. The data showed that nigericin was extremely sensitive to PC cells, and influenced the abilities of cell proliferation, colony formation, apoptosis, migration and invasion. The results in vitro implied that nigericin suppressed the Wnt/β-catenin signaling by upregulating PRKCA and HBP1 mRNA expressions. Si-PRKCA, si-HBP1 or silencing these two molecules simultaneously could attenuate the inactivation of Wnt/β-catenin signaling induced by nigericin. Furthermore, the dual strands of pre-miR-374b were proved to down-regulate the expressions of PRKCA and HBP1 coordinately through their mature products miR-374b-5p and -3p. Overexpression of pre-miR-374b might partly antagonize the suppressing effects of nigericin in PC cells. Suppressing the Wnt/β-catenin signaling pathway by targeting pre-miR-374b-PRKCA/HBP1 axis might represent a novel mechanism of nigericin in PC. Nigericin remained a candidate of preclinical application for PC.