Molecular Carcinogenesis最新文献

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.

Tumor metastasis and the persistence of cancer stem cells (CSCs) are the main factors contributing to tumor malignancy, particularly in breast cancer. Uncovering the critical molecular mechanisms and therapeutic targets is essential for addressing this challenge. The present study revealed that aquaporin-1 (AQP1) was highly expressed in breast cancer and was closely associated with poor patient prognosis. AQP1 overexpression significantly enhanced multiple cellular processes in breast cancer cells, including cell proliferation, migration, invasion, spheroid formation, and three-dimensional (3D) spheroid invasion. Moreover, AQP1 activated the Wnt/β-catenin signaling pathway, and promoted the expression of epithelial-mesenchymal transition (EMT)-related markers (N-cadherin and vimentin) and CSC markers (SOX2 and c-Myc). Furthermore, small hairpin (sh)RNA-mediated downregulation of β-catenin confirmed the mechanism by which AQP1 promoted EMT and CSC properties through the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present study elucidated the molecular mechanism through which AQP1 advanced breast cancer progression via the Wnt/β-catenin signaling pathway, providing insights into the mechanisms underlying breast cancer progression and offering valuable implications for developing novel therapeutic strategies.

Recently, RNA editing, as a natural modification process of RNA molecules, has aroused extensive interest in the scientific community. This study elaborated the role and process of A-to-I RNA edited miR-3167 in lung adenocarcinoma (LUAD). RT-qPCR and Western blot analysis were employed for the detection of miRNA and gene expressions. The function of miRNA was investigated through Transwell, CCK-8 and flow cytometry assays. Dual-luciferase reporter assay was conducted to assess the link between gene and miRNA. The level of A-to-I RNA editing for miR-3167 was declined in LUAD tissues, which was linked to adverse clinical outcomes and prognosis in LUAD patients. In LUAD, ADAR2 enzyme is responsible for mediating the A-to-I RNA editing of miR-3167. Functionally, LUAD cell viability and metastasis were scarcely influenced by wt-miR-3167, while miR-3167 displayed antitumor activity in LUAD post A-to-I RNA editing. Mechanically, SSR2 is directly targeted by ed-miR-3167 in LUAD, but not wt-miR-3167. SSR2 served as a tumor promoter in LUAD progression by inactivating Hippo signaling and hindering immune infiltration. Ed-miR-3167 exerted tumor inhibitory effect in LUAD by weakening the carcinogenesis of SSR2. A-to-I RNA edited miR-3167 curbs malignant behaviors of LUAD by activating Hippo signaling through downregulating SSR2, indicating that edited miR-3167 has the potential as a therapeutic target for LUAD.

Lung cancer is characterized by high aggressiveness and lethality, processing in-depth molecular mechanism investigation is particularly necessary. In our study, we found that osteoglycin (OGN) deficiency is strongly associated with a poor prognosis in lung adenocarcinoma (LUAD). OGN overexpression could inhibit the proliferation, migration, and invasion of LUAD cells. Through transcriptome sequencing analysis and experimental validation, we revealed that such OGN-mediated tumor suppression effect was related to cell adhesion function induced by ICAM1 downregulation, along with regulation by the PI3K/AKT signaling pathway. The present study demonstrated the specific mechanism of OGN involvement in LUAD progression, providing new evidence and potential targets for research on cancer suppression in LUAD.

Mitochondrial function plays a crucial role in cancer development, with mitochondrial energy metabolism-related genes (MEMRGs) contributing to carcinogenesis. This study investigates the role of MEMRGs in intrahepatic cholangiocarcinoma (ICC) by analyzing RNA-seq data from TCGA and GEO databases to identify differentially expressed MEMRGs. Functional enrichment and KEGG pathway analyses revealed their significant involvement in metabolic pathways. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, two distinct ICC subtypes were identified. Tumor mutational burden (TMB), immune cell infiltration, and immune escape potential were assessed, highlighting the importance of the Hippo/YAP pathway. Cox regression analyses pinpointed key prognostic genes, including ADH1A, ADH1B, and CYP4A11. A MEMRG-based nomogram was developed that accurately predicted 1- and 3-year survival outcomes. Experimental validation showed that ADH1B suppresses ICC malignancy through the Hippo/YAP pathway. These findings suggest that MEMRGs are vital in ICC progression and immune regulation, serving as promising prognostic biomarkers and therapeutic targets, though further validation is required.

Prostate cancer (PCa) is the second leading cause of cancer-related death among American men, and its long latency offers a window for chemopreventive strategies. Phytochemicals, with their diverse impacts on cancer cell growth and metabolism, represent promising candidates for such strategies. Combining compounds like curcumin (Curc) and ursolic acid (UA), which target multiple pathways, can be advantageous in slowing tumor progression. Previous studies revealed the synergistic effects of Curc + UA in reducing tumor growth in a PCa allograft model. In this study, diet-based interventions were evaluated using two transgenic mouse models of PCa. Mice fed a Curc + UA-enriched diet exhibited significant inhibition of prostate tumor progression compared to single-agent diets in both HiMyc and PTEN knockout mouse models. Protein analyses of ventral prostate tissues from HiMyc mice indicated that the combination suppressed oncogenic signaling pathways, including STAT3, AKT, and mTORC1, while modulating cell regulatory proteins to inhibit tumor cell proliferation. Furthert mechanistic studies in mouse and human PCa cell lines confirmed that Curc + UA exerted pleiotropic effects by influencing oncogenic signaling, cell cycle regulation, mitochondrial function, unfolded protein response (UPR), and apoptosis, collectively contributing to its synergistic efficacy. These findings highlight the potential of Curc + UA to inhibit PCa progression through multitargeted mechanisms. The combination's superior efficacy over single agents underscores its promise as a chemopreventive or therapeutic strategy. This study provides a strong rationale for further mechanistic investigations and clinical development of Curc + UA for PCa prevention and treatment.

Brain metastasis (BM), most vital and common metastasis phenotype occurs during tumorigenesis, the incidence of which varied remarkedly in various cancers. Overwhelming evidence suggested blood-brain barrier (BBB) can attenuate the anti-BM efficacy of chemotherapies via hindering their penetration. This study aimed to investigate the preferential cancer type that is more prone to BM, and bioactive compound that suppress BM through penetrating BBB. By intracardiac injection of lung cancer cells, breast cancer cells and melanoma cells, BM models were established. By two cycles of primary-isolation and incubation of H446-luc cells to improve the incidence of BM. Artemisinin (ART) and its derivatives were evaluated to suppress BM in vitro and in vivo. Compared to lung cancer-driven BM (66.67%), the incidence of BM in breast cancer (16.67%-33.33%) and melanoma (33.33%) were extremely low. The incidence of BM in lung cancer increased from 66.67 (1st generation) to 80% (2nd generation). Compared to other ingredients, artesunate (ARTS) exerted a more significant inhibitory effect on cell proliferation, especially in lung cancer cells. Simultaneously, ARTS suppressed lung cancer migration via decreasing N-cadherin and Snail, and enhancing E-cadherin. Most importantly, we found that ARTS could strikingly suppress tumor growth in brain with high concentration, implying that ARTS might penetrate BBB and accumulate in brain tissue to hinder lung cancer-driven BM. Our findings not only suggest lung cancer exhibited tumor specificity in cancer-driven BM model, but also provide ARTS as a promising candidate for clinical treatment of lung cancer-relayed BM.