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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.

The treatment of patients with CLL has undergone significant changes in recent years. Standard chemoimmunotherapy is changing to targeted inhibition with modern drugs. The listed drugs have better efficacy and significantly improve the overall survival of patients according to registry clinical studies. In a retrospective analysis, we evaluated 43 patients with CLL who underwent venetoclax treatment at the Hematology Department, University Hospital and Polyclinic F. D. Roosevelt Banská Bystrica, Slovakia (FNsP FDR BB) in 2019-2024. The aim of this work was to evaluate retrospectively the efficacy and safety of venetoclax in the treatment of patients with CLL. The median age of patients at the time of initiation of venetoclax treatment was 58 years, range 41-79 years. The majority of patients, 27 (63%) were men and 16 (37%) were women. Patients were treated with venetoclax in the first and higher line, in combination with obinutuzumab, with rituximab, and in monotherapy. Of these, 16 (37%) patients were after previous treatment with ibrutinib. Treatment indications and response assessment were based on the 2018 international workshop on the Chronic Lymphocytic Leukemia (iwCLL) Criteria. Patients were evaluated after at least 2 months of treatment until disease progression. The effect of treatment was assessed by objective examination of the patient, possibly by imaging examination (USG, CT scan) and evaluation of blood parameters. Adverse effects were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In case of disease progression, treatment was interrupted. The results of our work confirmed the efficacy and safety of venetoclax in combination with obinutuzumab, and rituximab, even as monotherapy in patients with CLL. The efficacy of the above regimens in our group of patients is comparable to that in clinical studies, even in patients with high-risk genetic features, such as 17p deletion and unmutated IgVH status. Treatment with venetoclax was also effective and well tolerated in patients after previous treatment with ibrutinib. The limitations of our evaluation are the small patient population and the short median follow-up of patients. In line with the conclusions of clinical trials and retrospective analysis from real-life practice, we can say that venetoclax-based treatment regimens are highly effective in patients with CLL in the first and higher line of treatment, with acceptable and well-manageable toxicity. This treatment is also effective in patients after previous treatment with ibrutinib.

Refractory diffuse gastric cancer (DGC) is rising in incidence and has a bad prognosis. Individuals who are administered second-line or subsequent therapies frequently exhibit diminished physical fitness, rendering them inappropriate for intensive treatment. Despite this, PD-1 inhibitors and anti-angiogenesis drug apatinib have demonstrated efficacy in advanced gastric cancer. This study aimed to evaluate the effectiveness, prognostic factors, and safety of PD-1 inhibitors in combination with apatinib in advanced DGC. The present study is a retrospective analysis of 34 patients with advanced DGC treated with apatinib combined with PD-1 inhibitors in the Affiliated Cancer Hospital of Zhengzhou University from 2019 to 2022. Apatinib 250 mg was administered to patients once a day. The median progression-free survival (mPFS) and the median overall survival (mOS) were estimated using Kaplan-Meier curves, whereas objective response rate (ORR), disease control rate (DCR), prognostic variables, and adverse events were among the other outcomes. Data from 34 patients were collected, and the ORR was 5.9% (2 out of 34), while the DCR was 55.9% (19 out of 34). The mPFS was 2.5 months (95% CI: 1.9-3.0), while the mOS was 6.8 months (95% CI: 3.7-9.9). Log-rank univariate analysis indicated that the mOS of patients with carcinoembryonic antigen (CEA) levels <4.7 ng/ml (11.3 months, 95% CI: 7.1-15.5) was significantly different from those with levels ≥4.7 ng/ml (2.7 months, 95% CI: 0.0-6.1) (p=0.008). A notable disparity in mOS and mPFS was observed between patients with CA125 <35 U/ml (7.7 months, 95% CI: 3.6-11.9) and those with CA125 ≥35 U/ml (2.5 months, 95% CI: 1.9-3.0) (p=0.003), as well as between patients with lactate dehydrogenase (LDH) <245 U/l (11.3 months, 95% CI: 7.2-15.5) and those with LDH ≥245 U/l (2.2 months, 95% CI: 1.5-2.9) (p=0.007), and between patients with PLTs <350×109/l (7.5 months, 95% CI: 6.4-8.7) compared to those with PLTs ≥350×109/l (1.7 months, 95% CI: 0.0-3.9) (p=0.001). Multivariate Cox regression analysis indicated that CA125, LDH, and PLT levels were independent prognostic variables. The occurrence of grade 3 or 4 treatment-related adverse events was 17.6% (6/34). The study suggests that the integration of PD-1 inhibitors and apatinib in second-line and subsequent therapies demonstrated promising efficacy and acceptable safety in advanced DGC patients. The concentrations of CA125, LDH, and PLTs may serve as prognostic indicators for DGC.