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Retinal G protein-coupled receptor (RGR) serves a retinal photoisomerase function to mediate retinoid metabolism and visual chromophore regeneration in the human eyes. Retinoids display critical functions in cell proliferation, differentiation, and apoptosis. Abnormal retinoid metabolism may contribute to tumor development. However, in human tumor tissues, the expression of RGR remains uncharacterized. Herein, we performed the analysis of RGR expression in 620 samples from 24 types of tumors by immunohistochemistry (IHC) and 33 cancer types from the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases by bioinformatic analyses. Furthermore, the biological role of RGR in glioma cells was investigated using molecular biology approaches in vitro. Notably, we found that brain lower grade glioma (LGG), in contrast to other tumor types, had the highest median score of IHC and RNA level of RGR expression. Survival analysis showed that low RGR expression was associated with worse overall survival in LGG (p<0.0001). RGR expression levels in glioma were also associated with pathological subtypes, grades, and isocitrate dehydrogenase (IDH) mutations. Moreover, its molecular function was closely associated with cadherin-related family member 1 (CDHR1), a tumor suppressive protein in glioma, suggesting that RGR might negatively regulate the tumorigenesis and progression of LGG through interacting with CDHR1. Our findings provide new insight into the role of RGR in human cancer, especially in glioma.

Programmed death-ligand 1 (PD-L1) is the most widely utilized predictive marker used to identify non-small cell lung carcinoma (NSCLC) patients most suitable for immunotherapy approaches. The relationship between PD-L1 expression, the presence of CD8+ T cells, and other clinicopathological characteristics of NSCLC patients has not been elucidated yet. In this retrospective study, we immunohistochemically determined PD-L1 expression (using clone 22C3) and CD8+ T cell count (using clone c8/144B) in surgical resection specimens from 698 advanced NSCLC patients. Results of PD-L1 expression and CD8+ T cell count were correlated to various clinicopathological characteristics, including the presence of desmoplasia in NSCLC. Regarding the immunological attributes of the tumor microenvironment, we identified major differences between desmoplastic and non-desmoplastic areas in NSCLC. Tumor areas without desmoplasia were significantly more often PD-L1 positive than tumor cell clusters encased in a dense collagenous stroma (p=0.004). Furthermore, the desmoplastic stroma contained significantly less often an immune cell infiltrate rich in CD8+ T cells (p<0.001). Also, the positivity of PD-L1 significantly correlated with advanced N-stage (p<0.001) and poor differentiation in adenocarcinomas (p=0.032) but not with other clinicopathological characteristics. In conclusion, to our knowledge, this is the first study that points to major differences in terms of immunological attributes between desmoplastic and non-desmoplastic areas in NSCLC. The desmoplastic component, therefore, may represent an immunologically distinct tumor area in which PD-L1 immunohistochemistry and CD8+ T cell count should be evaluated separately.

This study aimed to retrospectively evaluate the treatment strategies and possible prognostic factors in patients with brain metastases (BMs) from esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed 30 patients with BMs from ESCC who were treated at our center between November 2011 and January 2022. Clinicopathological characteristics and clinical outcomes were analyzed. The median follow-up time was 2 (range, 0.5-33) months. The median survival time after diagnosis of BMs was 2 months. The 1-year overall survival (OS) rate was 13.6%. The OS was better in patients with intracranial benefit. Multivariate analysis showed that local treatment of BMs influenced OS. The median survival with or without local treatment of BMs was 4 and 1 month, respectively. The median time interval between the diagnosis of the primary tumor and BMs was 11 (range, 1-156) months. Among these BMs, 55.6% of the BM occurred within the first year after diagnosis of the primary tumor, 66.7% in the first 2 years, and 85.2% in the first 3 years. The median time interval from lung metastasis to BMs was 3 months, from liver metastasis to BMs 3.5 months, and from bone metastasis to BMs 0.5 months. Local treatment of BMs was an independent prognostic factor for patients with BMs from ESCC. Earlier detection followed by an aggressive local therapeutic approach for BMs had a great influence on treatment outcomes as well as the long-term prognosis and quality of life for appropriately selected patients.

Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.

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Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by high invasiveness, metastasis, and poor prognosis, which lacks effective treatments. Although the role of miR-192 in HCC development has been recognized, the underlying molecular mechanism is still poorly understood. This study aimed to explore the impact of mir-192 on HCC and its potential as a therapeutic strategy. Wound healing assay, Transwell assay, CCK-8 assay, and flow cytometry were performed to detect the impact of miR-192 on HCC cell metastasis, invasion, proliferation, and apoptosis, respectively. q-PCR and western blot were applied to measure the relative mRNA and protein expression of the GSK3β/Wnt/β-catenin pathway in miR-192-overexpressing cell lines. Immunofluorescence was carried out to detect the nuclear translocation of β-catenin. starBase website and dual luciferase reporter assay were used to verify the interaction between miR-192 and the target gene WNT10B 3'-untranslated region (3'-UTR) of the Wnt pathway. In addition, we developed algin/polyethyleneimine@miR-192 (AG/PEI@miR-192) nanohydrogel for in vivo delivery of miR-192-agomir. The results revealed that overexpressed miR-192 reduced the expression of HCC cell surface markers CD90, EpCAM, and CD133. Moreover, miR-192 overexpression inhibited HCC cell metastasis, invasion, and proliferation, promoted cell apoptosis, and reduced GSK3β/Wnt/β-catenin pathway expression. Additionally, AG/PEI@miR-192 exhibited good drug release and tumor inhibition. In conclusion, our study suggested that miR-192 inhibits HCC development by suppressing the GSK3β/Wnt/β-catenin pathway and proposed a promising hydrogel-based miR-192 delivery approach to hinder tumor growth.

Existing evidences have revealed the crucial roles of E2 promoter binding factor-1 (E2F1) during the tumorigenesis and progression process of multiple human tumors. However, the expression patterns, biological functions, as well as the underlying molecular mechanism of E2F1 in endometrial carcinoma yet remain largely unclear. The expression patterns and clinical prognostic value of E2F1 in endometrial carcinoma were evaluated using bioinformatics methods. Protein and mRNA, miRNA expression levels in tissues and cells were measured using immunohistochemistry, western blotting, and qRT-PCR assays. Cell viability and cell cycle distribution were examined using CCK-8 assay and flow cytometry, respectively. Scratch healing assay and Transwell assay were applied to measure cell migration and invasion ability. Bioinformatic analysis and luciferase reporter assays were conducted to confirm the targeting relationship between E2F1 and miR-329-3p. Moreover, a series of in vitro and in vivo functional experiments were employed to evaluate the effect of the miR-329-3p/E2F1 axis on cell growth and metastasis. Clinically, E2F1 was aberrantly expressed in endometrial carcinoma tissues and was correlated with advanced FIGO stage, histological type, p53 mutation, poor survival, and degree of tumor cell differentiation. ROC curves analysis also reveals that E2F1 has a high AUC value (up to 0.952, 95% CI: 0.915-0.988), indicating the promising diagnostic value of E2F1 level in endometrial carcinoma. In addition, in vitro gain and loss-of-functional experiments verified that high E2F1 can promote cell proliferation, cell cycle, migration, invasion, and EMT process. In-depth mechanism studies revealed that E2F1 was a downstream target gene of miR-329-3p, and miR-329-3p overexpression could effectively abrogate its promotion of cell malignant biological behavior. Collectively, our findings suggested that the miR-329-3p/E2F1 axis plays a crucial role in the progression of endometrial carcinoma, indicating that E2F1 can be considered a promising diagnostic and prognostic biomarker for endometrial carcinoma patients.

The aim of this study was to explore the role and mechanism of long non-coding RNA (lncRNA) HIF1A antisense RNA 2 (HIF1A-AS2) in regulating imatinib (IM) resistance in gastrointestinal stromal tumor (GIST) cells under hypoxia. The expression of HIF1A-AS2 was silenced by siRNA in GIST cells. Cytotoxicity, apoptosis, and autophagy were evaluated under normoxic and hypoxic conditions. The expression levels of HIF1A-AS2, HIF1A, apoptosis-associated genes, and autophagy-associated genes were determined by qRT-PCR analysis and western blot. We found that lncRNA HIF1A-AS2 was highly expressed in GIST tissues and cells. Knockdown of HIF1A-AS2 increased the sensitivity of GIST cells to IM and increased apoptosis. Moreover, a hypoxic environment decreased the sensitivity of GIST cells to IM, and the knockdown of HIF1A-AS2 reversed this effect. Mechanistically, the knockdown of HIF1A-AS2 inhibited IM-mediated autophagy. Finally, HIF1A was found to positively regulate HIF1A-AS2 under hypoxic conditions. Collectively, these data demonstrate that hypoxia-induced HIF1A-AS2 promotes IM resistance in GIST cells by regulating autophagy.

Gut microbial dysbiosis persists months after intensive cancer treatment in children and adolescents. This prospective study compared the intestinal microbiome of children 1-3 years after completion of Berlin-Frankfurt-Münster protocol (BFM)-based pediatric ALL (PALL) treatment and healthy controls. To induce a favorable shift in the bacterial composition of the intestines in PALL with gut microbiome disruptions, 8 weeks of physical activity and probiotic consumption were used. Blood analyses and 16S rRNA sequencing for the gut microbiome were performed on 16 pediatric cases and 16 healthy controls. Significant differences in bacterial diversity were found between pre- and post-intervention, respectively (Shannon index, 3.22±0.45 vs. 3.47±0.24, p=0.04; Simpson index, 0.10±0.05 vs. 0.06±0.02, p=0.02; and Chao1 index, 693.88±238.58 vs. 794.23±116.34, p=0.04). Furthermore, the increase in the relative abundance of Lactobacillus casei (5.04E-03±1.62E-02 vs. 2.92E-02±5.03E-02, p=0.04) and the increase in some strains of Veillonella, a bacterial genus recently linked to improved physical fitness, were identified. Promisingly, the exercise program combined with dairy probiotics increased bacterial richness and diversity.

Although a phase II clinical trial confirmed that camrelizumab combined with apatinib is effective in patients with hepatocellular carcinoma (HCC), we generally lack data on the results of this regimen in real-world clinical practice. In this study, the efficacy and safety of camrelizumab combined with apatinib in the treatment of patients with HCC were re-evaluated. Data from 86 patients with HCC were collected and combinatorically treated with camrelizumab and apatinib at the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. The objective remission rate and disease control rate were 25.6% and 72.1%, respectively. The median progression-free survival was 5 months (95% CI 3.7-6.3 months), and the median overall survival time was 19.0 months (95% CI 16.9-21.1 months). The 12- and 18-month survival rates were 70.9% and 54.2%, respectively. The most common grade 3-4 adverse events were hypertension (24.4%), thrombocytopenia (16.3%), and hyperbilirubinemia (9.3%). Multivariate regression analysis showed that operation history was an independent risk factor for overall survival.