Cancer Biology & Therapy最新文献

Keratin 80 (KRT80) is a filament protein that makes up one of the major structural fibers of epithelial cells, and involved in cell differentiation and epithelial barrier integrity. Here, KRT80 mRNA expression was found to be higher in esophageal cancer than normal epithelium by RT-PCR and bioinformatics analysis (p < .05), opposite to KRT80 methylation (p < .05). There was a negative relationship between promoter methylation and expression level of KRT80 gene in esophageal cancer (p < .05). KRT80 mRNA expression was positively correlated with the differentiation, infiltration of immune cells, and poor prognosis of esophageal cancer (p < .05). KRT80 mRNA expression was positively linked to no infiltration of immune cells, the short survival time of esophageal cancers (p < .05). The differential genes of KRT80 mRNA were involved in fat digestion and metabolism, peptidase inhibitor, and intermediate filament, desosome, keratinocyte differentiation, epidermis development, keratinization, ECM regulator, complement cascade, metabolism of vitamins and co-factor (p < .05). KRT-80-related genes were classified into endocytosis, cell adhesion molecule binding, cadherin binding, cell-cell junction, cell leading edge, epidermal cell differentiation and development, T cell differentiation and receptor complex, plasma membrane receptor complex, external side of plasma membrane, metabolism of amino acids and catabolism of small molecules, and so forth (p < .05). KRT80 knockdown suppressed anti-apoptosis, anti-pyroptosis, migration, invasion, chemoresistance, and lipogenesis in esophageal cancer cells (p < .05), while ACC1 and ACLY overexpression reversed the inhibitory effects of KRT80 on lipogenesis and chemoresistance. These findings indicated that up-regulated expression of KRT80 might be involved in esophageal carcinogenesis and subsequent progression, aggravate aggressive phenotypes, and induced chemoresistance by lipid droplet assembly and ACC1- and ACLY-mediated lipogenesis.

Drug resistance is a critical impediment to efficient therapy of diffuse large B-cell lymphoma (DLBCL) patients. Recent studies have highlighted the association between ferroptosis and drug resistance that has been reported. Fatty acid synthase (FASN) is always related to a poor prognosis. In this study, we investigate the impact of FASN on drug resistance in DLBCL and explore its potential modulation of ferroptosis mechanisms. The clinical correlation of FASN mRNA expression was first analyzed to confirm the role of FASN on drug resistance in DLBCL based on the TCGA database. Next, the impact of FASN on ferroptosis was investigated in vitro and in vivo. Furthermore, a combination of RNA-seq, western blot, luciferase reporter, and ChIP experiments was employed to elucidate the underlying mechanism. The prognosis for patients with DLBCL was worse when FASN was highly expressed, particularly in those undergoing chemotherapy for Adriamycin (ADM). FASN promoted tumor growth and resistance of DLBCL to ADM, both in vitro and in vivo. It is noteworthy that this effect was achieved by inhibiting ferroptosis, since Fer-1 (a ferroptosis inhibitor) treatment significantly recovered the effects of silencing FASN on inhibiting ferroptosis, while Erastin (a ferroptosis inducer) treatment attenuated the impact of overexpressing FASN. Mechanistically, FASN activated NF-κB/STAT3 signaling pathway through phosphorylating the upstream IKKα and IκBα, and the activated STAT3 promoted GPX4 expression by directly binding to GPX4 promoter. FASN inhibits ferroptosis in DLBCL via NF-κB/STAT3/GPX4 signaling pathway, indicating its critical role in mediating ADM resistance of DLBCL.

Background: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism.

Methods: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model.

Results: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth.

Conclusion: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.

In this study, we aimed to investigate the molecular mechanism of Krüppel-like factor 7 (KLF7) in colorectal cancer (CRC) cell invasion and migration. The expression pattern of KLF7 in CRC tissues and the correlation between KLF7 expression and clinical symptoms of CRC were analyzed. CRC cell lines were transfected with si-KLF7, followed by qRT-PCR or western blot detection of KLF7, miR-139-5p, and tumor protein D52 (TPD52) expression, cell counting kit-8 (CCK-8) assay to detect cell viability, and transwell detection of invasion and migration. Chromatin immunoprecipitation (ChIP) analyzed the enrichment KLF7 in the miR-139-5p promoter. The dual-luciferase reporter assay verified the binding relationship between KLF7 and miR-139-5p, and between miR-139-5p and TPD52. In the subcutaneous tumorigenesis experiment, tumor growth was observed and ki67-positive expression was detected. KLF7 is abundantly expressed in CRC cells KLF7 silencing inhibits CRC cell viability, invasion, and migration. KLF7 represses miR-139-5p expression by binding to the miR-139-5p promoter. miR-139-5p targets TPD52 expression. miR-13-5p inhibition or TPD52 overexpression partially counteracted the effect of KLF7 silencing in CRC cells. KLF7 silencing suppresses tumor growth in vivo. In conclusion, KLF7 suppresses miR-139-5p expression by binding to the miR-139-5p promoter, thereby upregulating TPD52 expression and enhancing CRC cell invasion and migration.

Metastasis accounts for the vast majority of cancer deaths; however, this complex process has yet to be fully explained. To form metastases, cancer cells must undergo a series of steps, known as the "Metastatic cascade", each of which requires a specific functional transformation. Cancer stem cells (CSCs) play a vital role in tumor metastasis, but their dynamic behavior and regulatory mechanisms have not been fully elucidated. Based on the "Metastatic cascade" theory, this review summarizes the effect of liver CSCs on the metastatic biological programs that underlie the dissemination and metastatic growth of cancer cells. Liver CSCs have the capacity to initiate distant organ metastasis via EMT, and the microenvironment transformation that supports the ability of these cells to disseminate, evade immune surveillance, dormancy, and regenerate metastasis. Understanding the heterogeneity and traits of liver CSCs in these processes is critical for developing strategies to prevent and treat metastasis of advanced hepatocellular carcinoma (HCC).

Double minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

Cervical cancer (CC) is a prevalent malignancy among women worldwide. This study was designed to investigate the role of METTL14 in sorafenib-induced ferroptosis in CC. METTL14 expression and m6A methylation were determined in CC tissues, followed by analyzes correlating these factors with clinical features. Subsequently, METTL14 was knocked down in CC cell lines, and the effects on cell proliferation, mitochondrial morphology and ferroptosis were assessed using CCK-8, microscopy, and markers associated with ferroptosis, respectively. The regulatory relationship between METTL14 and FTH1 was verified using qRT-PCR and luciferase reporter assays. The functional significance of this interaction was further investigated both in vitro and in vivo by co-transfecting cells with overexpression vectors or shRNAs targeting METTL14 and FTH1 after sorafenib treatment. METTL14 expression and m6A methylation were significantly reduced in CC tissues, and lower METTL14 expression levels were associated with a poorer CC patients' prognosis. Notably, METTL14 expression increased during sorafenib-induced ferroptosis, and METTL14 knockdown attenuated the ferroptotic response induced by sorafenib in CC cells. FTH1 was identified as a direct target of METTL14, with METTL14 overexpression leading to increased m6A methylation of FTH1 mRNA, resulting in reduced stability and expression of FTH1 in CC. Furthermore, FTH1 overexpression or treatment with LY294002 partially counteracted the promotion of sorafenib-induced ferroptosis by METTL14. In vivo xenograft experiments demonstrated that inhibiting METTL14 reduced the anticancer effects of sorafenib, whereas suppression of FTH1 significantly enhanced sorafenib-induced ferroptosis and increased its anticancer efficacy. METTL14 reduces FTH1 mRNA stability through m6A methylation, thereby enhancing sorafenib-induced ferroptosis, which contributes to suppressing CC progression via the PI3K/Akt signaling pathway.

Breast cancer ranks the first in the incidence of female cancer and is the most common cancer threatening the life and health of women worldwide.Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) is a pro-apoptotic gene downstream of p53. However, the role of TP53AIP1 in BC needs to be investigated. In vitro and in vivo experiments were conducted to assess the biological functions and associated mechanisms. Several bioinformatics analyses were made, CCK8 assay, wound healing, transwell assays, colony formation assay, EDU, flow cytometry, Immunofluorescence, qRT-PCR and Western-blotting were performed. In our study, we discovered that BC samples had low levels of TP53AIP1 expression, which correlated with a lower survival rate in BC patients. When TP53AIP1 was up-regulated, it caused a decrease in cell proliferation, migration, and invasion. It also induced epithelial-to-mesenchymal transition (EMT) and protective autophagy. Furthermore, the over-expression of TP53AIP1 suppressed tumor growth when tested in vivo. We also noticed that TP53AIP1 up-regulation resulted in decreased levels of phosphorylation in AKT and mTOR, suggesting a mechanistic role. In addition, we performed functional rescue experiments where the activation of AKT was able to counteract the impact of TP53AIP1 on the survival and autophagy in breast cancer cell lines. This suggests that TP53AIP1 acts as an oncogene by controlling the AKT/mTOR pathway. These findings reveal TP53AIP1 as a gene that suppresses tumor growth and triggers autophagy through the AKT/mTOR pathway in breast cancer cells. As a result, TP53AIP1 presents itself as a potential target for novel therapeutic approaches in treating breast cancer.