Carcinogenesis最新文献

In recent decades, considerable evidence has emerged indicating the involvement of tRNA-derived fragments (tRFs) in cancer progression through various mechanisms. However, the biological effects and mechanisms of tRFs in lung adenocarcinoma (LUAD) remain unclear. In this study, we screen out tRF-29-79, a 5'-tRF derived from tRNAGlyGCC, through profiling the tRF expressions in three pairs of LUAD tissues. We show that tRF-29-79 is downregulated in LUAD and downregulation of tRF-29-79 is associated with poorer prognosis. In vivo and in vitro assay reveal that tRF-29-79 inhibits proliferation, migration and invasion of LUAD cells. Mechanistically, we discovered that tRF-29-79 interacts with the RNA-binding protein PTBP1 and facilitates the transportation of PTBP1 from nucleus to cytoplasm, which regulates alternative splicing in the 3' untranslated region (UTR) of SLC1A5 pre-mRNA. Given that SLC1A5 is a core transporter of glutamine, we proved that tRF-29-79 mediate glutamine metabolism of LUAD through affecting the stability of SLC1A5 mRNA, thus exerts its anticancer function. In summary, our findings uncover the novel mechanism that tRF-29-79 participates in glutamine metabolism through interacting with PTBP1 and regulating alternative splicing in the 3' UTR of SLC1A5 pre-mRNA.

Hepatocellular carcinoma (HCC) exhibits a high mortality rate due to its high invasion and metastatic nature, and the acidic microenvironment plays a pivotal role. Acid-sensing ion channel 1 (ASIC1) is upregulated in HCC tissues and facilitates tumor progression in a pH-dependent manner, while the specific mechanisms therein remain currently unclear. Herein, we aimed to investigate the underlying mechanisms by which ASIC1 contributes to the development of HCC. Using bioinformatics analysis, we found a significant association between ASIC1 expression and malignant transformation of HCC, such as poor prognosis, metastasis and recurrence. Specifically, ASIC1 enhanced the migration and invasion capabilities of Li-7 cells in the in vivo experiment using an HCC lung metastasis mouse model, as well as in the in vitro experiments such as wound healing assay and Transwell assay. Furthermore, our comprehensive gene chip and molecular biology experiments revealed that ASIC1 promoted HCC migration and invasion by activating the PRKACA/AP-1 signaling pathway. Our findings indicate that targeting ASIC1 could have therapeutic potential for inhibiting HCC progression.

Long non-coding RNAs (lncRNAs) have been established as pivotal players in various cellular processes, encompassing the regulation of transcription, translation and post-translational modulation of proteins, thereby influencing cellular functions. Notably, lncRNAs exert a regulatory influence on diverse biological processes, particularly in the context of tumor development. Tumor-associated macrophages (TAMs) exhibit the M2 phenotype, exerting significant impact on crucial processes such as tumor initiation, angiogenesis, metastasis and immune evasion. Elevated infiltration of TAMs into the tumor microenvironment (TME) is closely associated with a poor prognosis in various cancers. LncRNAs within TAMs play a direct role in regulating cellular processes. Functioning as integral components of tumor-derived exosomes, lncRNAs prompt the M2-like polarization of macrophages. Concurrently, reports indicate that lncRNAs in tumor cells contribute to the expression and release of molecules that modulate TAMs within the TME. These actions of lncRNAs induce the recruitment, infiltration and M2 polarization of TAMs, thereby providing critical support for tumor development. In this review, we survey recent studies elucidating the impact of lncRNAs on macrophage recruitment, polarization and function across different types of cancers.

The role of RNA methylation is vital in the advancement and spread of tumors. However, its exact role in microsatellite instability in colorectal cancer (CRC) is still not fully understood. To address this gap in knowledge, this study investigated the impact of genes associated with RNA methylation on the prognosis and response to immunotherapy in individuals diagnosed with low microsatellite instability (MSI-L) or microsatellite stable (MSS) CRC. The differentially expressed genes (DEGs) in two groups of patients: those with high microsatellite instability (MSI-H) and those with MSI-L/MSS was thoroughly investigated and compared with aims of exploring the association between them and the 60 RNA methylation regulators. We employed these genes and developed an MSI-RMscore to establish a risk signature capable of forecasting patient outcomes. Furthermore, an investigation of the immunophenotypic traits was conducted encompassing patients categorized as high-risk and low-risk. By combining the MSI-RMscore and clinicopathological features, a predictive nomogram was developed, which was subsequently validated using the GEO database. Furthermore, immunohistochemistry was employed to establish the correlation between INHBB and SOWAHA and the MSI status, as well as patient prognosis. Our findings indicated that the high-risk subgroup exhibited unfavorable overall survival rates, reduced responsiveness to immune checkpoint blockers, elevated estimate scores, and increased infiltration of macrophages and fibroblasts. We also confirmed that INHBB and SOWAHA were associated with CRC patient prognosis and MSI status, as well as immunotherapy response. These findings suggest that targeting INHBB and SOWAHA could be a promising strategy to enhance patient responsiveness to immunotherapy.

Tripartite Motif 14 (TRIM14) is an oncoprotein that belongs to the E3 ligase TRIM family, which is involved in the progression of various tumors except for non-small cell lung carcinoma (NSCLC). However, little is currently known regarding the function and related mechanisms of TRIM14 in NSCLC. Here, we found that the TRIM14 protein was downregulated in lung adenocarcinoma tissues compared with the adjacent tissues, which can suppress tumor cell proliferation and migration both in vitro and in vivo. Moreover, TRIM14 can directly bind to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), which in turn results in the degradation of GFAT1 and reduced O-glycosylation levels. GFAT1 is a key enzyme in the rate-limiting step of the hexosamine biosynthetic pathway (HBP). Replenishment of N-acetyl-d-glucosamine can successfully reverse the inhibitory effect of TRIM14 on the NSCLC cell growth and migration as expected. Collectively, our data revealed that TRIM14 suppressed NSCLC cell proliferation and migration through ubiquitination and degradation of GFAT1, providing a new regulatory role for TRIM14 on HBP.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.

Tumor-associated macrophages (TAMs) are among the most abundant cell types in the tumor microenvironment (TME). The immunosuppressive TME formed by TAMs is an essential prerequisite for cancer progression. Tumor-derived microvesicles (MVs), a subtype of extracellular vesicle shed directly from the plasma membrane, are important regulators of intercellular communication and TME modulation during tumorigenesis. However, the exact mechanism by which tumor-derived MVs induce the generation of the immunosuppressive TME and polarization of TAMs remains unclear. Here, we investigated the role of CD133-containing MVs derived from colorectal cancer (CRC) cells in macrophage polarization and cancer progression. CD133-containing MVs from CRC cells were incorporated into macrophages, and M0 macrophages were morphologically transformed into M2-like TAMs. CD133-containing MVs were found to increase the mRNA expression of M2 macrophage markers. Additionally, cytokine array analysis revealed that M2-like TAMs induced by CD133-containing MVs increased the secretion of interleukin 6, which activated the STAT3 pathway in CRC cells. Furthermore, the conditioned medium of M2-like TAMs promoted cell motility, epithelial-mesenchymal transition, and cell proliferation. However, MVs from CD133-knockdown cells had little effect on TAM polarization and CRC progression. These results demonstrate that CD133-containing MVs induce M2-like TAM polarization and contribute to cancer progression by mediating crosstalk between tumor cells and TAMs in the TME of CRC.

The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein and CO2, all of which occur in high concentrations in cigarette smoke, are discussed.

Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (n = 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from The Cancer Genome Atlas to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (P = 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (P = 0.036) and progression-free survival, and higher durable clinical benefit and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune-related genes. Gene set enrichment analysis showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.