Translational Oncology最新文献

Objective

Despite its involvement in regulating various cellular functions, the expression and role of WD repeat-containing protein 77 (WDR77) in cancer remain elusive. This study aims to explore the expression and potential roles of WDR77 across multiple cancers, with a particular focus on its relevance in colorectal cancer (CRC).

Methods

We obtained WDR77 RNA-seq data, mutations, CNVs, and DNA methylation data from the TCGA, GTEx, and GEO databases to investigate its expression patterns and prognostic value. Additionally, we examined the correlation between WDR77 expression and somatic mutations, copy number variations, DNA methylation, and mRNA modifications. We utilized GSVA, GSEA algorithms, and CRISPR KO data from the Dependency Map database to explore WDR77′s potential biological functions. The association between WDR77 and the tumor immune microenvironment was investigated using ESTIMATE and IOBR algorithms. Finally, we assessed WDR77 expression in CRC and its impact on cell proliferation through qRT-PCR, Western blotting, immunohistochemistry, CCK8, colony formation, and EdU assays.

Results

WDR77 was upregulated in various tumors and correlated with poor patient prognosis. Its high expression positively correlated with pathways related to cell proliferation and negatively correlated with immune-related pathways. In CRC, WDR77 expression was associated with specific clinical features, genomic alterations, and immune microenvironment characteristics. Experimental validation confirmed upregulated WDR77 expression in CRC tissues and cells, with WDR77 knockdown significantly inhibiting CRC cell proliferation.

Conclusion

WDR77 holds potential as an oncogene and biological marker in various cancers, particularly CRC.

Introduction

: Small cell lung cancer (SCLC) is mostly diagnosed in stage III-IV patients and associated with poor prognosis. To date, surgery is no gold-standard treatment for any SCLC stage and evidence is lacking whether it is beneficial. Here we investigate the impact of surgery, with special attention to stage III SCLC patients, sub-stages and treatment combinations.

Methods

: The overall survival (OS) and cancer-specific survival (CSS) of 33,198 SCLC patients (SEER database) were analyzed retrospectively, using various statistical analyses, including propensity score matching (PSM), recursive partitioning, and sequential landmark analyses.

Results

: Independent of stage, the OS of patients with surgery-including treatments was almost always better than without surgery. This holds true for stage I-II patients, even after PMS analysis (p < 0.017). The same was found for stage IV patients that underwent surgery plus chemotherapy vs. chemotherapy alone (p = 0.013 after PSM). Stage III patients showed a robust improvement in OS and CSS after surgery (OS: 18 vs.13 months) or surgery plus chemotherapy (OS: 20 vs.15 months) as confirmed by well-balanced PSM and sequential landmark analyses of long-term survivors. More detailed analyses using two independent approaches showed prolonged OS in T3–4/N0–1 and T1–2/N2 stage III patients after surgery or surgery plus chemotherapy. Importantly, primary site surgery had a major survival advantage over surgery at regional sites (p < 0.003).

Conclusion

: Our study demonstrates that selected patients of all stages, including stage III T3–4/N0–1 and T1–2/N2, can benefit greatly from surgery-including treatments. Thus, surgery should be included into hospital treatment recommendations for specifically selected SCLC patients.

Condensed abstract

Primary resection in patients with stage III SCLC needs re-evaluation. Selected patients with stage III SCLC benefit significantly from surgery. Patients with T3–4/N0–1 and T1–2/N2 stage III SCLC should be considered for surgery.

Current prognostic biomarkers fall short in stratifying Oestrogen receptor (ER)-negative breast cancer patients regarding tumour progression risk at diagnosis. The role of AIPL1 in activating its tumour suppressor client protein, NEDD8 Ultimate Buster-1 (NUB1) remains unknown in cancer. Our study demonstrated how downregulated AIPL1 results in the deactivated NUB1 protein under hypoxic conditions. We examined the AIPL1-NUB1 pathwayin vitro using cell lines i.e. MCF-7, MDA-MB-231, RCC4 etc. NUB1 expression was assessed using Oncomine, and cBioPortal was performed to assess NUB1′s prognostic significance in human cancers. In the John Radcliffe Hospital cohort (n = 122), immunohistochemistry analysis revealed downregulated AIPL1 (Log2 fold change=-0.28; p < 0.001) and upregulated NUB1 transcripts (Log2 fold change=0.59; p < 0.001) compared to adjacent normal tissues. In severe chronic hypoxia, multimerised AIPL1 localisedin the cytoplasm while NUB1 protein migrated to the nucleus, where the absence of NUB1 nuclear localisation led to cell cycle arrest. Biopsies showed that patients with lower cytoplasmic NUB1 expression (n = 57) had poorer overall survival compared to those with higher cytoplasmic expression (n = 57), HR=1.78; 95 % CI=1.01–3.35, p = 0.048. Low NUB1 protein levels in both normoxic and hypoxic conditions were associated with cell cycle arrest and upregulation ofp21 and p27 in breast cancer cell lines, correlating significantly withpoorer survival outcomes in all breast cancer and ER-negative breast cancer patients.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high pathogenicity and extremely poor prognosis. The role of circular RNAs (circRNAs) in HCC carcinogenesis and progression remains to be determined. Based on the analysis of HCC-related databases, as well as the expression analysis and identification of 25 HCC patient tissues and HCC cell lines, we found that the hsa_circ_0031431 (circCOCH) is significantly highly expressed in HCC tissues and cell lines. High circCOCH expression is associated with enhanced tumor proliferation and metastasis, and knocking down circCOCH can inhibit the growth of HCC in vivo and in vitro. Mechanistic studies show that circCOCH upregulates the expression of epidermal growth factor receptor (EGFR) through sponge miR-450a, thereby activating the Phosphoinositide 3-kinases (PI3Ks) cell pathway to promote HCC proliferation and metastasis. Futhermore, we found that IGF2BP3 mediates the biogenesis of circCOCH. The present study provides innovative insights into the role of circRNAs in the etiology of HCC carcinogenesis and might serve as a new promising therapeutic target for HCC.

Background

Mammary carcinoma is the most frequently diagnosed form of carcinoma in women worldwide. The organometallic compounds showed a prospective anticancer activity. This research explored the anticancer efficacy of taxifolin ruthenium-p-cymene counter to breast cancer.

Methods

The anticancer efficacy of the novel organometallic compound was investigated via various in vitro and in vivo techniques using breast cancer cell lines and breast cancer model of rat.

Results

Target proteins were identified via pharmacophore analysis, which revealed a high binding affinity towards AhR, EGFR, and β-catenin. The compound induced apoptotic events and prevented cancer cell colony formation. Furthermore, decreased expression of AhR, EGFR, and N-cadherin inhibited cancer cell growth, migration, and proliferation. The compound provoked the cell cycle arrest at sub G0/G1 phase, S phase and G2/M phase and inaugurated the caspase-3 dependent apoptotic events. The in-vivo experimentation displayed the fruitful restoration of breast tissue since the complex treatment in DMBA persuaded breast carcinoma in rat. Moreover, the upstream of p53 and caspase-3 expression along with substantially downstream of vimentin, β-catenin, m-TOR and Akt expression.

Conclusions

In conclusion, the compound repressed the cancerous cellular viability, migration, and EMT via modulating the AhR/EGFR/ PI3K transduction pathway and the expression of EMT biomarkers such as N-cadherin, E-cadherin, thus eventually revoked the EMT facilitated metastasis of malignant cells.

Clinical genomic profiling of cell-free nucleic acids (e.g. cell-free DNA or cfDNA) from blood and other body fluids has ushered in a new era in non-invasive diagnostics and treatment monitoring strategies for health conditions and diseases such as cancer. Genomic analysis of cfDNAs not only identifies disease-associated mutations, but emerging findings suggest that structural, topological, and fragmentation characteristics of cfDNAs reveal crucial information about the location of source tissues, their epigenomes, and other clinically relevant characteristics, leading to the burgeoning field of fragmentomics. The field has seen rapid developments in computational and genomics methodologies for conducting large-scale studies on health conditions and diseases – that have led to fundamental, mechanistic discoveries as well as translational applications. Several recent studies have shown the clinical utilities of the cfDNA fragmentomics technique which has the potential to be effective for early disease diagnosis, determining treatment outcomes, and risk-free continuous patient monitoring in a non-invasive manner. In this article, we outline recent developments in computational genomic methodologies and analysis strategies, as well as the emerging insights from cfNA fragmentomics. We conclude by highlighting the current challenges and opportunities.

Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancers. In NSCLC, 10–20 % of Caucasian patients and 30–50 % of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9–18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands via a STAT3-dependent mechanism(s). Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs.

Tumor cells voraciously consume nutrients from their environment to facilitate rapid proliferation, necessitating effective strategies to manage nutrient scarcity during tumor growth and progression. A pivotal regulatory mechanism in this context is the Integrated Stress Response (ISR), which ensures cellular homeostasis under conditions such as endoplasmic reticulum stress, the unfolded protein response, and nutrient deprivation. Within the ISR framework, the kinase GCN2 is critical, orchestrating a myriad of cellular processes including the inhibition of protein synthesis, the enhancement of amino acid transport, autophagy initiation, and angiogenesis. These processes collectively enable tumor survival and adaptation under nutrient-limited conditions. Furthermore, GCN2-mediated pathways may induce apoptosis, a property exploited by specific therapeutic agents. Leveraging extensive datasets from TCGA, GEO, and GTEx projects, we conducted a pan-cancer analysis to investigate the prognostic significance of GCN2 expression across diverse cancer types. Our analysis indicates that GCN2 expression significantly varies and correlates with both adverse and favorable prognoses depending on the type of cancer, illustrating its complex role in tumorigenesis. Importantly, GCN2 also modulates the tumor immune microenvironment, influencing immune checkpoint expression and the functionality of immune cells, thereby affecting immunotherapy outcomes. This study highlights the potential of targeting GCN2 with specific inhibitors, as evidenced by their efficacy in preclinical models to augment treatment responses and combat resistance in oncology. These findings advocate for a deeper exploration of GCN2′s multifaceted roles, which could pave the way for novel targeted therapies in cancer treatment, aiming to improve clinical outcomes.

Background

Synthetic lethality (SL) emerges as a novel concept being explored to combat cancer progression and resistance to conventional therapy. Despite the efficacy of chemotherapy in select cases of colorectal cancer (CRC), a substantial proportion of patients encounter challenges, leading to an adverse prognosis of CRC patients. CRC-related SL genes offer a potential avenue for identifying therapeutic targets.

Methods

CRC-related SL genes were obtained from the SynLethDB database. The bulk RNA sequencing data, mutation data, and clinical information for treated and untreated CRC patients were enrolled from the UCSC and GEO databases. The Tumor Immunology Single Cell Center database served as the repository for collecting and analyzing single-cell RNA sequencing data. The synergistic killing effect of SL genes and chemotherapeutic drugs on resistant cells was experimentally verified.

Results

In the present study, pivotal SL genes associated with chemoresistance identified by using WGCNA and CRC patients categorized into two groups based on these genes. Variations between the groups were most pronounced in pathways associated with extracellular matrix remodeling. Further by integrating mutation data, five potential SL genes were discerned, which were highly expressed in the presence of TP53 or KRAS mutations, leading to a severely poor prognosis. Subsequent time series analysis revealed that the expression of GTF2H5 was gradually elevated at different stages of the transition from sensitive to resistant in CRC cells. Finally, it was preliminarily verified by experiments that GTF2H5 may play a key role in driving the drug-resistant transition within CRC cells.

Conclusions

The identification of SL genes that collaboratively interact with chemotherapeutic agents could provide new insights into solving the issue of chemotherapy resistance in CRC patients. And GTF2H5 wields a fundamental influence in inducing chemoresistance in CRC, which provided a potential therapeutic target for CRC.

This study investigates the expression and functional roles of SUGT1 in ovarian cancer, utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Our analyses reveal that SUGT1 is significantly upregulated in ovarian cancer tissues compared to normal controls. We further explore the prognostic value of SUGT1, where elevated expression correlates with poorer patient outcomes, particularly in ovarian cancer. The functional implications of SUGT1 in cancer biology were assessed through in vitro and in vivo experiments. Gene Set Enrichment Analysis (GSEA) indicates a significant association between high SUGT1 expression and the activation of glycolytic pathways, suggesting a potential role in metabolic reprogramming. Inhibition of SUGT1 via siRNA in ovarian cancer cell lines results in decreased proliferation and increased apoptosis, along with reduced migration and invasion capabilities. Additionally, our study identifies the transcription factor ELF1 as a significant regulator of SUGT1 expression. Through promoter analysis and chromatin immunoprecipitation, we demonstrate that ELF1 directly binds to the SUGT1 promoter, enhancing its transcription. This regulatory mechanism underscores the importance of transcriptional control in cancer metabolism, providing insights into potential therapeutic targets. Our findings establish SUGT1 as a crucial player in the oncogenic processes of ovarian cancer, influencing both metabolic pathways and transcriptional regulation. This highlights its potential as a biomarker and therapeutic target in managing ovarian cancer.