Neoplasma最新文献

Triptonide, an active ingredient of Tripterygium wilfordii Hook. F., has been found to have anticancer effects on various cancers; however, its effect on oral squamous cell carcinoma (OSCC) has not yet been studied. This study aims to reveal the effect and mechanism of triptonide on OSCC. The inhibitory effect of triptonide on OSCC progression was ascertained by CCK-8 assay, EdU incorporation assay, wound healing assay, Transwell assay, and xenograft tumor model, while western blotting, qRT-PCR, and immunohistochemistry revealed that triptonide could inhibit c-Myc expression in OSCC. RNA-seq was conducted to explore the mechanism by which triptonide inhibited the progression of OSCC, and thyroid hormone receptor interactor 13 (TRIP13) was identified as a key differentially expressed gene. TRIP13-knockdown OSCC cells constructed with siRNA showed weaker progression ability in CCK-8 assay, EdU incorporation assay, wound healing assay, and Transwell assay. Finally, TRIP13-overexpressing OSCC cells constructed through plasmid were used in rescue experiments, which demonstrated that TRIP13 was located upstream of c-Myc and the overexpression of TRIP13 could partially restore the decreased c-Myc expression caused by triptonide treatment. Collectively, this study demonstrated that triptonide might reduce the expression of c-Myc by suppressing TRIP13 expression, thereby inhibiting the progression of OSCC. These findings have revealed a partial mechanism by which triptonide acts on OSCC and suggested its potential application value in OSCC treatment.

Kelch-like family member 7 (KLHL7) is associated with cancer development and occurrence, but its role and mechanism in the malignant progression of gliomas remain poorly understood. This study aimed to investigate the regulatory effects and mechanisms of KLHL7 on cell cycle and glutamine metabolism in glioma. Glioma cell lines A172 and U87 and a xenograft mouse model were used to analyze the function of KLHL7 in vitro and in vivo, respectively. Gene expression levels and protein amounts were assessed by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability was assessed using the CCK-8 assay, and the cell cycle was analyzed via flow cytometry. The glutamine content was measured using a biochemical assay. The level of KLHL7 was upregulated in patients with glioma. KLHL7 knockdown reduced cell viability, inhibited cell cycle progression, and decreased the glutamine content in A172 cells. KLHL7 silencing inhibited tumor growth in vivo. Furthermore, KLHL7 overexpression enhanced cell viability, cell cycle progression, and glutamine metabolism and activated the β-catenin signaling pathway in U87 cells. These findings indicate that KLHL7 promotes the malignant progression of glioma via the β-catenin signaling pathway and may serve as a biomolecule for the clinical prediction and treatment of the disease.

To reduce the burden of colorectal cancer (CRC), the chemopreventive effects of 1-year metformin on polyps or adenoma recurrence in patients without diabetes mellitus (DM) who underwent polypectomy were evaluated. Patients without DM aged between 40 and 70 years old, with no polyp or adenoma after polypectomy, were randomly assigned to the control (no intervention), low-dose (500 mg/day), or high-dose (1,000 mg/day) metformin groups in a 1:1:1 ratio. After the 1-year intervention, the numbers of polyps and adenomas were measured and recorded, then resected. Plasma lipid and blood glucose were measured at baseline and 1-year follow-up. Data from the three groups were compared statistically. A total of 272 patients were enrolled in the analysis. In the control group, 48.9% of patients had adenoma recurrence, which was significantly higher than those in the low-dose (30.8%, p=0.012) and the high-dose (29.9%, p=0.009) metformin group. For the number of recurrent adenomas per subject, the difference between the control and the high-dose metformin groups was significant (0.86±1.09 vs. 0.47±0.83, p=0.020). No significant difference among the three groups and between baseline and 1-year follow-up was found in the lipid and glucose parameters. In conclusion, 1-year metformin use reduced the prevalence of recurrent adenoma significantly in patients without DM after polypectomy and may not be related to lipid and glucose metabolism.

In cervical cancer, the regulatory mechanisms of CD47 and its enrichment in exosomes have not been fully elucidated. In this study, we aim to explore the mechanisms of how EGFR/STAT3 signaling regulates CD47 expression in cervical cancer, and whether p65 or RAB31 is involved in this process. RNA interference was used to knock down the fragment of HPV in cervical cancer cells. EGFR and RAB31 phosphorylation were detected by western blot, and exosomal CD47 was determined by ELISA. EGFR or STAT3 was then knocked down and western blot was used to detect the expression or phosphorylation of EGFR, STAT3, p65, CD47, RAB31, and its related proteins. ChIP-qPCR was used to investigate p65 enrichment in the CD47 promoter region. Our results showed that HPV fragment knockdown reduced the phosphorylation of EGFR and RAB31, and exosomal CD47 expression. Knocking down EGFR inhibited phosphorylation of STAT3 and p65, and expression of RAB31-related proteins. Phosphorylated p65 was bound to the P3 and P7 promoter regions of CD47. EGFR/STAT3 signaling upregulated CD47 expression by phosphorylating p65 and enhanced exosomal CD47 by activated RAB31. Thus, a dual regulatory role of EGFR/STAT3 signaling on CD47 expression and secretion involving transcriptional factor p65 and exosome transporter RAB31 was demonstrated.

The mammalian target of rapamycin (mTOR) is a critical sensor and integrator of extracellular stimuli and intracellular signaling pathways, forming structurally and functionally distinct protein complexes (mTORC1, mTORC2, and mTORC3) with various proteins. It serves as a central regulator of vital biological processes like cell proliferation, survival, and autophagy. Numerous studies have linked mTOR pathway activation to tumor progression. DEPTOR, a common negative regulator of mTORC1 and mTORC2, exhibits complex loop regulatory mechanisms beyond simple mTOR pathway modulation. Depending on the cell type or tissue environment, DEPTOR can act as either an oncogene or a tumor suppressor gene. Given its complex role in tumorigenesis, precise regulation of DEPTOR expression across different tumor types is imperative. DEPTOR has emerged as a key focus in research on human malignant tumors. While recent years have seen through investigations into DEPTOR expression regulation in tumors, a systematic literature review is lacking. This review provides a detailed summary of the mechanisms regulating DEPTOR expression, an mTOR inhibitor in tumors, covering DNA induction, transcription, translation, and post-translational modification. Additionally, it explores the potential applications of DEPTOR/mTOR signaling axis-related compounds in tumor therapy.

Tyrosine kinase inhibitors (TKIs) like gefitinib, which target the epidermal growth factor receptor (EGFR), show considerable therapeutic effectiveness in non-small cell lung cancer (NSCLC) with EGFR-activating mutations. Nevertheless, the resistance that develops against EGFR-TKIs diminishes their therapeutic impact in clinical settings. This investigation focused on the impact of eukaryotic translation initiation factor 4E (eIF4E) on gefitinib resistance in NSCLC. Using the CCK-8 assay, the influence of different gefitinib concentrations on cell proliferation was examined. eIF4E and EGFR expressions were verified by qRT-PCR and/or western blotting in NSCLC cell lines. Moreover, the effects of eIF4E knockdown in gefitinib-treated PC9/GR cells were detected by CCK-8, flow cytometry, colony formation assays, and xenograft tumor model. eIF4E expression was remarkably upregulated in the gefitinib-resistant PC9/GR cells. Moreover, the expression levels of eIF4E in NSCLC cell lines exhibited a dose-dependent increase following gefitinib administration. The function assays demonstrated that reducing eIF4E levels hindered the proliferation of PC9/GR cells and enhanced the apoptosis-inducing effects of gefitinib both in vitro and in vivo, and also had an inhibitory action on the Wnt/β-catenin pathway. Taken together, these results suggested that eIF4E confers gefitinib resistance in NSCLC by regulating the Wnt/β-catenin pathway. Therefore, eIF4E is a possible therapeutic target for improving therapeutic action in NSCLC patients who have developed resistance to gefitinib.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with increasing morbidity and mortality. Heat shock transcription factor 1 (HSF1), as an important transcription factor regulating the expression of heat shock proteins, has been proven to play a crucial role in the development of various tumors. Yet the potential mechanism and clinical significance of HSF1 in CRC remain unclear and require further exploration. We used TCGA database to understand the clinical significance of HSF1 in CRC. Then, we verified the expression of HSF1 in CRC tissues by immunohistochemistry and analyzed its clinical significance. By constructing stable knockdown and overexpressed of HSF1 in cell lines to investigate the potential mechanisms of HSF1 to regulate CRC cell proliferation, migration, and invasion in vivo and in vitro. Next, differential genes expressed by HSF1 in CRC were analyzed by bioinformatics technology, and their correlation and interaction were verified by PCR, WB, and CHIP experiments. We confirmed that HSF1 is highly expressed in CRC and its upregulation is associated with poor prognosis of malignant events in CRC. Functionally, HSF1 can enhance the proliferation, invasion, and migration of CRC cell lines. In vivo experiments have shown that knockdown of HSF1 can inhibit tumor growth. In terms of molecular mechanism, we found that HSF1 can directly bind to the transcription factor binding site of CLDN3 and activate its transcription. Our research demonstrates the clinical significance and carcinogenic effect of HSF1. The functional mechanisms of HSF1 and its targets may serve as diagnostic and therapeutic targets for CRC.

Despite advances in chemoradiotherapy and hematopoietic stem cell transplantation, the treatment of acute myeloid leukemia (AML) remains challenging due to significant side effects and poor prognosis. This study aimed to investigate the role of nuclear factor I-C (NFIC) in AML progression by evaluating whether NFIC exacerbates AML through the inhibition of SRY-box transcription factor 1 (SOX1) and activation of autophagy, thereby providing potential insights for clinical treatment. NFIC and SOX1 expression levels in AML and normal samples were analyzed using bioinformatics, ELISA, RT-qPCR, and western blotting, and the interaction between NFIC and SOX1 was assessed through RNA pull-down and RNA-binding protein immunoprecipitation assays. Moreover, CCK-8 assay, FITC/PI apoptosis detection, immunofluorescence staining, RT-qPCR, and western blotting were conducted to assess cell viability, apoptosis, and the expression of NFIC, SOX1, Bax, Bcl-2, LC3-I, LC3-II, p62, and Beclin-1 following gene transfection. NFIC expression was significantly upregulated in AML samples while SOX1 expression was downregulated compared to normal controls. High NFIC levels were associated with poor prognosis in AML patients, and it was found to regulate SOX1 expression in KG-1 and NB4 cells negatively. Silencing NFIC or overexpressing SOX1 resulted in reduced cell viability and autophagy, and increased apoptosis in KG-1 and NB4 cells. Importantly, NFIC knockdown did not affect apoptosis in bone marrow mononuclear cells. The adverse effects of NFIC overexpression were reversed by SOX1 overexpression, highlighting the interplay between these factors in AML. This study demonstrates that NFIC promotes AML progression by activating autophagy and suppressing apoptosis in KG-1 and NB4 cells by inhibiting SOX1, providing a potential basis for therapeutic strategies targeting NFIC and SOX1 in AML.

The aim of the present study was to examine the impact of LS-102, an inhibitor of enzymatic activity of HRD1 that is an essential E3 ubiquitin ligase of endoplasmic reticulum associated degradation (ERAD) on survival of the human cell lines derived from glioblastoma multiforme (GBM), neuroblastoma, and astrocytes. We have also examined molecular responses to HRD1 inhibition with a focus on proteins playing an essential role in unfolded protein response (UPR) and ERAD. In addition, activation of IRE1α documented by XBP1 splicing was investigated. Finally, we have examined the impact of LS-102 on p53 expression in GBM cells. Inhibition of HRD1 enzymatic activity results in cell death of all tested cells. With respect to GBM cells, U87 cells are more sensitive to LS-102 as T98G cells. Cells of cell lines derived from normal astrocytes K1884 exhibit the highest sensitivity to LS-102 among all cell types used in the study while NHA cells are the most resistant. Sensitivity of neuroblastoma SH-SY5Y cells to LS-102 is comparable to the sensitivity of U87 cells. In GBM cells, inhibition of HRD1 results in induction of the expression of proteins playing an essential role in UPR and ERAD (HRD1, SEL1L, and GRP78). XBP1 splicing induced by HRD1 inhibition was documented in T98G and K1884 cells. We did not observe induction of p53 expression in U87 cells. Since LS-102 induces cell death of normal astrocytes, it is not a candidate for the testing of its potential use as an antitumor treatment of GBM.

Necroptosis is a programmed form of necrosis, and compounds inducing necroptosis may contribute to cancer treatment. 20(S)-ginsenoside Rg3 is a natural compound extracted from ginseng, which exhibited a broad-spectrum of antitumor activity. In the present study, the potential role of 20(S)-ginsenoside Rg3 in inducing necroptosis in prostate cancer cells was evaluated. 20(S)-ginsenoside Rg3 inhibited the proliferation of prostate cancer cells and upregulated the expression of necroptotic proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, and their downstream mixed lineage kinase domain-like protein (MLKL). Pretreatment with the selective RIPK1 inhibitor necrostatin-1 (Nec-1) partially reversed the inhibitory effect of 20(S)-ginsenoside Rg3 on prostate cancer cell proliferation. 20(S)-ginsenoside Rg3 led to the accumulation of reactive oxygen species (ROS) and the regulation of autophagy in cancer cells. Scavenging ROS with N-acetyl-L-cysteine (NAC) antagonized the regulatory effects of 20(S)-ginsenoside Rg3 on cell autophagy and necroptotic proteins expression. Moreover, 20(S)-ginsenoside Rg3 exhibited an antitumor effect in a prostate cancer xenograft mouse model in which it upregulated the expression of RIPK1, RIPK3, MLKL and led to a decrease in tumor weight, as well as an increase in necrotic areas in tumor tissue. In conclusion, our study showed that 20(S)-ginsenoside Rg3 might induce necroptosis in prostate cancer in vitro and in vivo via the ROS/autophagy signaling pathway.