OncoTargets and therapy最新文献

Background: Multiple Myeloma (MM) is the second most common hematologic malignancy, which exhibits strong resistance to bortezomib, the first-line treatment. Circular RNAs (circRNAs) are increasingly considered as important drivers of drug resistance across various cancers, but their roles in multiple myeloma are not well understood.

Aim: To investigate and identify potential circRNA targets and their roles in the mechanisms of bortezomib resistance.

Methods: Bortezomib-resistant MM patient-specific circRNAs were screened using Arraystar circRNA microarrays. The MM circRNA dataset from the GEO database was analyzed with GEO2R to identify candidate circRNAs associated with MM progression and drug resistance. CircRNA-forming and loop-forming sites, along with their structures, were identified via Sanger sequencing. The identified circRNA was validated by qRT-PCR in MM patients with and without bortezomib resistance. Bioinformatic analysis through CircInteractome was conducted to predict potential miRNA and RBP binding for the core circRNAs. Metascape was employed to perform RBP pathway analysis to identify specific biological processes in circRNAs.

Results: The hsa_circ_0058191 was found to be overexpressed in bortezomib-resistant MM patient samples, suggesting its pivotal role in drug resistance mechanisms. The interaction of hsa_circ_0058191 with miR-660 and AGO2 as determined through bioinformatic predictions, indicated that it regulates RNA modification and mRNA regulation pathways. These molecular interactions expand our understanding of the mechanisms of drug resistance in multiple myeloma.

Conclusion: This study identified the role of hsa_circ_0058191 in the development of drug resistance in MM, which provides a theoretical foundation for designing potential therapeutic strategies to prevent drug resistance.

Background and objective: Cystic lung cancer (CLC) presents diagnostic and treatment challenges due to its complex imaging features and unclear molecular mechanisms. Although surgery and standard chemotherapy are frequently used, there is limited information on targeted therapy and other precision treatments. It is crucial to comprehensively understand the molecular mechanisms and explore precision treatments based on targeted therapy.

Methods: Topic keywords including "CLC", "cystic lung cancer", "cavitary lung cancer", "Lung cancer associated with cystic airspaces", and "lung cancer" with ("sac cavity" OR "cystic degeneration" OR "thin-walled cavity" OR "adenocystic carcinoma" OR "cystic airspaces" OR "pulmonary cysts" OR "adenoid cystic carcinoma") searched in the relevant databases, such as PubMed, Google Scholar, and CNKI (China National Knowledge Infrastructure). Then, we reviewed and analyzed the molecular mechanism and its precision therapeutics of CLC.

Key content and findings: Various subtypes of CLC can be identified through histopathological examination, such as cystic adenocarcinoma, and squamous cell carcinoma. However, we still have much to learn about the molecular mechanisms behind CLC. Gene mutation, the abnormal tumor microenvironment, and immune dysfunction are the main mechanisms, along with potential factors like epigenetic modifications and gene susceptibility related to COPD. Recent advancements in treatment include targeted therapies, such as targeted inhibitors for EGFR, ALK, ROS1, BRAF, and MET. Surgical treatment, standardized chemotherapy, immunotherapy, and combination therapy remain important. Future research should focus on genomic and molecular profiling, and the development of precision medicine based on insights into the heterogeneity of CLC. Additionally, investigating resistance mechanisms and developing predictive biomarkers are important for future CLC research.

Conclusion: The key molecular mechanisms of CLC involve gene mutations and TME immune dysfunction. CLC still requires standard comprehensive treatment based on lung cancer staging, and targeted therapy has shown significant advantages and development prospects.

Breast cancer is one of the most common malignant tumours in women worldwide. A primary route for breast cancer cells to disseminate is through regional lymphatic vessels and nodes. Cancer cell-induced lymphangiogenesis plays a crucial role in lymphatic metastasis and is associated with poor survival of breast cancer. Advances in molecular biology have led to the identification of biomarkers associated with lymphangiogenesis and lymphatic metastasis, including lymphatic vessel endothelial cell (LVEC) markers and tumour microenvironment markers, such as vascular endothelial growth factor receptor 3 (VEGFR3), podoplanin (PDPN), and lymphatic endothelial hyaluronan receptor-1 (LYVE1). LVEC molecular markers play a profound role in both the formation of new lymphatic vessels and the invasive expansion of primary tumour. Abnormal expression of LVEC markers may contribute to lymphatic vessel disease and/or metastasis of cancer cells through the lymphatic system. These molecular markers may present a potential for targeted therapies and precision diagnostics for managing lymphatic metastasis in breast cancer. This review aims to provide a comprehensive summary of the current understanding of the molecular and cellular machinery underlying lymphatic metastasis in breast cancer, with a particular focus on the lymphangiogenic markers and their role in the lymphatic dissemination.

Objective: The study investigated microRNA-152-3p-mediated autophagy and sensitivity of paclitaxel-resistant ovarian cancer cells.

Methods: The miR-152-3p mimics and miR-152-3p inhibitor were transfected in A2780 cells and A2780T cells, and the scrambled sequences were transfected as a negative control group, the transfection efficiency was detected by qPCR technology. MTT was used to detect the proliferation and IC50 value of the cells after transfection. The expression of target proteins in A2780 cells and A2780T cells were detected by qPCR; The expression of phosphatase and tensin homolog (PTEN) and ATG4D after transfection were analyzed by Western blot. The knockdown efficiency of PTEN was detected by reverse qRT-PCR, MTT and Western blot.

Results: The expression level of miR-152-3p in A2780T cells was 52-fold higher than that in A2780 cells according to the results of qPCR. Downregulation of miR-152-3p reversed PTX-induced autophagy, inhibited cell proliferation and apoptosis, and reduced drug resistance in A2780T cells. Moreover, PTEN appeared to be a potential target of miR-152-3p, and low expression levels of miR-152-3p increased PTX sensitivity by downregulating PTEN in vitro.

Conclusion: PTEN may be a novel therapeutic target gene for patients with PTX-resistant ovarian cancer. These findings provide a potential translational framework for developing novel therapeutic strategies to overcome paclitaxel resistance in ovarian cancer.

Background: Cancer remains a major global health challenge, with early detection and prompt treatment being crucial for reducing mortality rates. The SPINK4 has been linked to the development of several tumors, and there is growing evidence of its involvement. However, its specific functions and effects in different cancer types remain unclear.

Methods: The association between SPINK4 expression levels and tumor progression was investigated and confirmed using the TCGA dataset. Kaplan-Meier curves were utilized to examine the correlation between SPINK4 expression with survival outcomes in pan-cancer patients. The Pearson method was employed to investigate the association of SPINK4 expression with the tumor microenvironment, stemness score, immunoinfiltrating subtype, and chemotherapy sensitivity in human different cancer types. Wound healing and Transwell assays were performed to confirm the roles of the model gene in colon adenocarcinoma cells.

Results: The expression of SPINK4 shows heterogeneity across pan-cancer tissues, and is closely associated with poor prognosis, immune cell invasion, tumor cell resistance, and tumor metastasis in a various human cancer. Mutation of SPINK4 hold significant predictive value for poor prognosis of pan-cancer patients. In addition, SPINK4 expression was significantly correlated with the tumor microenvironment (stromal cells and immune cells) and stemness score (DNAss and RNAss) in human pan-cancer tissues, particularly in BLCA and COAD. Single-cell sequencing analysis showed that SPINK4 is mainly expressed in endothelial cells in BLCA and in malignant cells in COAD. Drug resistance analysis showed a significant association between SPINK4 expression and sensitivity to several cancer chemotherapy drugs. Importantly, overexpression of SPINK4 promoted the metastasis of colon cancer cell lines (HCT116 and RKO), whereas SPINK4 knockout markedly inhibited their metastasis.

Conclusion: These findings reveal the crucial role of SPINK4 in the pan-cancer process and may have significant implications for the diagnosis and treatment of cancer in the future.

The KRAS gene is nearly ubiquitously subjected to activating mutation in pancreatic adenocarcinomas (PDAC), occurring at a frequency of over 90% in tumors. Mutant KRAS drives sustained signaling through the MAPK pathway to affect frequently disrupted cancer phenotypes including transcription, proliferation and cell survival. Recent research has shown that PDAC tumor growth and survival required a guanine nucleotide exchange factor for RAS homolog family member A (RhoA) called GEF-H1. The GEF-H1 protein, encoded by the ARHGEF2 gene, is a microtubule-associated GEF for RhoA that promotes invasion-migration of PDAC cells via activation of RhoA. Unexpectedly, independent of its RhoGEF activity, GEF-H1 was found to potentiate MAPK signaling by scaffolding protein phosphatase 2A (PP2A) to the kinase suppressor of Ras 1 (KSR-1). In a feedback-dependent manner, enhanced MAPK activity drives expression of ARHGEF2 via regulation of transcription factors ETS and SP, and the RAS responsive element-binding protein 1 (RREB1). RREB1 a negative regulator of ARHGEF2 expression, is downregulated in PDAC cells, which permits sustained expression of GEF-H1 for PDAC tumor survival and subsequent MAPK pathway activation. Given that MAPK targeted therapies show limited clinical efficacy, highlights the need for novel targets. This review describes the unexpected complexity of GEF-H1 function leading to positive feedback that potentiates RAS-MAPK signaling and suggests inhibition of GEF-H1 as a therapeutic strategy for RAS-driven cancers.

Background: Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion is crucial for autophagy, making YKT6, a key modulator of cell membrane fusion, a potential target for cancer therapy. However, its oncogenic role across different cancers remains unclear. This study was to investigate the prognostic value and potential immunological functions of YKT6, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).

Methods: Multiple bioinformatics databases, including The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) databases, were used to investigate the correlation of the YKT6 expression pattern with the pathological stage and survival rate across cancers. Furthermore, ImmuCellAI, the UCSC Xena platform, and the ESTIMATE algorithm were subsequently utilized to explore the potential relationship between YKT6 expression, the tumor microenvironment, and tumor immune infiltration. Profiling of YKT6 gene mutation and amplification, methylation, and copy number alteration (CNA) was performed on the basis of the TCGA database. Moreover, q-PCR, TMA staining, and siRNA assays were used to validate the cancer-promoting role of YKT6 in CESCs.

Results: Our results reveal that YKT6 is a potential prognostic and cancer immunity biomarker. Elevated YKT6 expression is correlated with poor overall survival (OS) and disease-free survival (DFS). Distinct gene mutation, methylation, and CNA patterns for YKT6 were found in certain types of cancers. The correlation of YKT6 expression with tumor-infiltrating immune cells was verified by analyzing the StromalScore, ESTIMATEScore, ImmuneScore, and tumor purity. In vitro analysis confirmed that YKT6 was highly expressed in advanced-grade CESCs and that the knockdown of YKT6 inhibited the proliferation of cervical cancer cells.

Conclusion: The SNARE protein YKT6 serves as a biomarker and candidate oncogene with actionable mutations. Moreover, YKT6 has the potential to be a prognostic indicator in CESCs. Targeting YKT6 could enhance autophagy regulation and improve therapeutic strategies for personalized cancer treatment.

Objective: To explore the relationship and underlying mechanisms between vitamin D and CRC, offering valuable insights into the diagnosis and treatment of CRC.

Materials and methods: Serum levels of 1,25(OH)₂D₃ were measured using a double-antibody sandwich assay. Bioinformatics analysis identified vitamin D-related CRC genes, which were validated using HCT116 and HT29 cell lines. Changes in hub gene expression were analyzed via RT-qPCR.

Results: Serum levels of 1,25(OH)₂D₃ were 42.99±6.02µg/mL in the normal group, 37.06±9.56µg/mL in the CRA group, and 19.00±5.96µg/mL in the CRC group (p<0.05). No significant differences were observed in VDR SNPs among the groups. Significant expression differences were detected in vitamin D-related colon cancer genes across the groups. LASSO regression analysis identified 5 key genes. The diagnostic model based on these genes demonstrated high diagnostic efficiency and performed well in the TCGA-COAD dataset. RT-qPCR results showed that SOSTDC1, PRKAA2, and CEACAM1 expressions decreased in the CRC and CRA groups, while MMP1 and CCND1 expressions increased. In vitro experiments indicated that calcitriol inhibits the proliferation and migration of HCT116 and HT29 cell lines and significantly alters the expression of hub genes.

Conclusion: Serum vitamin D levels are significantly lower in CRC patients. Vitamin D has been shown to inhibit the proliferation and migration of colon cancer cells and reduce the expression of oncogenes. Therefore, vitamin D holds substantial potential for the diagnosis and treatment of CRC.

NK cells are a type of antitumor immune cell with promising clinical application, following T cells. The activity of NK cells is primarily regulated by their surface receptors and immune microenvironment. In gliomas, the tumor microenvironment exerts a strong immunosuppressive effect, which significantly reduces the clinical efficacy of NK cell immunotherapy. Therefore, this review aims to discuss the latest research on the role of NK cells in glioma immunotherapy, focusing on aspects such as NK cell development, function, and localization. It summarizes information on the compounds, monoclonal antibodies, and cytokine therapies targeting NK cells while emphasizing the current status and trends of gene-modified NK cells in glioma treatment. Additionally, it explores the molecular mechanisms underlying immune escape in glioma cells, providing a theoretical foundation and new perspectives for NK cell-based immunotherapy in gliomas.

Purpose: To investigate the prognostic value of the pretreatment serum carcinoembryonic antigen (CEA) level in patients with rectal cancer treated by preoperative short-course radiotherapy (SCRT) followed by chemotherapy and delayed surgery.

Patients and methods: Two hundred and sixty-six consecutive patients with locally advanced rectal adenocarcinoma without distant metastasis receiving preoperative radiotherapy were enrolled. Group 1 patients (n=144) received long-course radiotherapy (LCRT) with 50.4 Gy in 28 fractions using photon radiotherapy (XRT). Group 2 patients (n=122) received SCRT with 25 Gy in 5 fractions using XRT or proton beam therapy (PBT) followed by chemotherapy and delayed surgery. Pathological complete response (pCR), near pathological complete response (npCR), locoregional recurrence (LRR), distant metastasis (DM), disease-specific survival (DSS) and overall survival (OS) rates were estimated and compared to scrutinize the prognostic significance of factors including CEA level.

Results: In group 1, higher CEA level (≥ 7 ng/mL) was a significant negative prognostic factor of pCR (p = 0.003, OR: 0.133), OS (p = 0.011, HR: 2.999), DM (p = 0.008, HR: 2.569), LRR (p = 0.044, HR: 3.160), and DSS (p = 0.015, HR: 3.273). In group 2, higher CEA level (≥ 7 ng/mL) was a significant negative prognostic factor of pCR (p = 0.002, OR: 0.038), OS (p < 0.001, HR: 44.658), DM (p < 0.001, HR: 8.926), LRR (p = 0.028, HR: 8.570), and DSS (p = 0.001, HR: 43.918). The npCR rates for clinical T4 patients were 6.5% and 22.0% (p = 0.032), in group 1 and group 2, respectively.

Conclusion: This study elucidates the prognostic merit of the pretreatment serum CEA level in patients with rectal cancer treated by either preoperative LCRT or SCRT followed by chemotherapy and delayed surgery.