Neoadjuvant SBRT combined with immunotherapy in NSCLC: from mechanisms to therapy.

The utilisation of neoadjuvant immunotherapy has demonstrated promising preliminary clinical outcomes for early-stage resectable non-small-cell lung cancer (NSCLC). Nevertheless, it is imperative to develop novel neoadjuvant combination therapy regimens incorporating immunotherapy to further enhance the proportion of patients who derive benefit. Recent studies have revealed that stereotactic body radiotherapy (SBRT) not only induces direct tumour cell death but also stimulates local and systemic antitumour immune responses. Numerous clinical trials have incorporated SBRT into immunotherapy for advanced NSCLC, revealing that this combination therapy effectively inhibits local tumour growth while simultaneously activating systemic antitumour immune responses. Consequently, the integration of SBRT with neoadjuvant immunotherapy has emerged as a promising strategy for treating resectable NSCLC, as it can enhance the systemic immune response to eradicate micrometastases and recurrent foci post-resection. This review aims to elucidate the potential mechanism of combination of SBRT and immunotherapy followed by surgery and identify optimal clinical treatment strategies. Initially, we delineate the interplay between SBRT and the local tumour immune microenvironment, as well as the systemic antitumour immune response. We subsequently introduce the preclinical foundation and preliminary clinical trials of neoadjuvant SBRT combined with immunotherapy for treating resectable NSCLC. Finally, we discussed the optimal dosage, schedule, and biomarkers for neoadjuvant combination therapy in its clinical application. In conclusion, the elucidation of potential mechanism of neoadjuvant SBRT combined immunotherapy not only offers a theoretical basis for ongoing clinical trials but also contributes to determining the most efficacious therapy scheme for future clinical application.

IncRNA EPB41L4A-AS1 Mitigates the Proliferation of Non-Small-Cell Lung Cancer Cells through the miR-105-5p/GIMAP6 Axis.

Non-small-cell lung cancer (NSCLC) is the major subtype of lung cancer, with a series of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and proteins involved in its pathogenesis. This study sought to investigate the functionality of lncRNA EPB41L4A antisense RNA 1 (lncRNA EPB41L4A-AS1) in the proliferation of NSCLC cells and provide a novel theoretical reference for NSCLC treatment. Levels of lncRNA EPB41L4A-AS1, miR-105-5p, and GTPase, IMAP family member 6 (GIMAP6) in tissues and cells were measured by RT-qPCR and the correlation between lncRNA EPB41L4A-AS1 and clinicopathological characteristics was analyzed. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. The subcellular localization of lncRNA EPB41L4A-AS1 was analyzed by the subcellular fractionation assay and the binding of miR-105-5p to lncRNA EPB41L4A-AS1 or GIMAP6 was analyzed by dual-luciferase and RNA pull-down assays. Functional rescue experiments were performed to analyze the role of miR-105-5p/GIMAP6 in NSCLC cell proliferation. lncRNA EPB41L4A-AS1 and GIMAP6 were downregulated while miR-105-5p was upregulated in NSCLC tissues and cells. lncRNA EPB41L4A-AS1 was correlated with tumor size and clinical staging and its overexpression reduced NSCLC cell proliferation. lncRNA EPB41L4A-AS1 was negatively correlated with miR-105-5p and positively correlated with GIMAP6 in NSCLC tissues, and lncRNA EPB41L4A-AS1 sponged miR-105-5p to promote GIMAP6 transcription in NSCLC cells. Overexpression of miR-105-5p or knockdown of GIMAP6 reversed the inhibition of lncRNA EPB41L4A-AS1 overexpression on NSCLC cell proliferation. lncRNA EPB41L4A-AS1 was downregulated in NSCLC and mitigated NSCLC cell proliferation through the miR-105-5p/GI-MAP6 axis.

The Effect of Hypoxia-Induced Exosomes on Anti-Tumor Immunity and Its Implication for Immunotherapy.

Hypoxia is a critical feature of solid tumors and is considered to be a key factor in promoting tumorigenesis and progression. Beyond inducing metabolic reprogramming of tumor cells to adapt to the hypoxia tumor microenvironment (TME), hypoxia can also promote tumor growth by affecting the secretion of exosomes. Exosomes are nano-sized (30-150 nm in diameter) extracellular vesicles that can carry numerous substances including lipids, proteins, nucleic acids, and metabolites. Notably, hypoxia-induced exosomes alterations not only exist in tumor cells, but also in various TME cells including stromal cells and immune cells. Besides promoting tumor invasion, angiogenesis, and drug resistance, the secretion of these altered exosomes has recently been found to negatively regulate anti-tumor immune responses. In this review, we focus on the hypoxia-induced changes in exosome secretion and found it can contributes to immune evasion and cancer progression by recruiting protumor immune cells into TME, as well as inhibiting antitumor immune cells. Next, we also describe the recent advances of exosomes in immunotherapy and future direction. In conclusion, ongoing discoveries in this field have brought new insights into hypoxia exosome-led immunosuppression, enabling the development of exosome-based therapeutics and elucidating their potential in immunotherapy.

Transactivation of PTGS2 by PAX5 signaling potentiates cisplatin resistance in muscle-invasive bladder cancer cells.

Cisplatin (CDDP)-based systematic chemotherapy remains the mainstay of treatment for muscle-invasive bladder cancer (MIBC). However, acquired resistance to CDDP, a multifactorial process governed by an array of signals acting at different levels, is the major problem in BC treatment. Here, we report for the first time that, expression of Paired-box gene 5 (PAX5), a B-cell essential transcription factor, was significantly induced in CDDP-resistant BC tissues and in experimentally-induced CDDP-resistant BC cells. Inhibition of PAX5 expression by shRNA treatment effectively improved CDDP sensitivity in BC cells, whereas overexpression of PAX5 potentiated CDDP resistance through supporting BC cell survival. Mechanistically, using luciferase reporter and chromatin immunoprecipitation assays, we identified prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2), a potent enzyme responsible for prostanoids formation and inflammatory response, as the direct down-stream target of PAX5. PAX5 exerted its oncogenic function during the pathogenesis of CDDP resistance via stimulation of PTGS2 transcription. These observations collectively suggest that dysregulation of PAX5/PTGS2 cascade plays a causal role in the induction of CDDP resistance and gene silencing approaches targeting this pathway may therefore provide a novel therapeutic strategy for overcoming CDDP resistance in BC.

High Levels of TRIM14 Are Associated with Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Tripartite motif containing 14 (TRIM14) has been reported to play a critical role in tumor development. However, little is known about TRIM14 expression and its clinical significance in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the expression and prognostic value of TRIM14 in patients with HCC. MATERIALS AND METHODS: The mRNA and protein levels of TRIM14 in HCC were evaluated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The association of TRIM14 expression with clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) was analyzed. RESULTS: TRIM14 expression was significantly upregulated in HCC-related tissues. High TRIM14 expression correlated with C-reactive protein (p = 0.01), alanine aminotransferase (p = 0.02), tumor size (p = 0.005), lesion number (p = 0.023), vascular invasion (p = 0.041), tumor/node/metastasis (TNM) stage (p = 0.001), and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.003). In addition, high TRIM14 expression was associated with poor OS and RFS (both p < 0.001). Cox regression analysis revealed that high TRIM14 expression was an independent prognostic factor for both OS (hazard ratio (HR) 1.657, 95% confidence interval (CI) 1.031-2.687; p = 0.018) and RFS (HR 2.297, 95% CI 1.184-2.312; p = 0.007). CONCLUSION: TRIM14 is a potential prognostic predictor for OS and RFS in patients with HCC.

Deregulation of WNT2/FZD3/ß-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome.

Mechanistic insight into estrogen deficiency by polycystic ovary syndrome (PCOS) remains a longstanding challenge in reproductive medicine. Recent advance suggest that Wingless-type MMTV integration site family members (WNTs), in concert with its Frizzled (FZD) receptors, regulate normal folliculogenesis, luteogenesis and ovarian steroidogenesis. However, no studies have so far investigated any causality between WNT-FZDs interactions and disrupted estrogen synthesis under certain pathological conditions. Here, we show that (i) FZD3 expression was significantly up-regulated in the cumulus cells (CCs) from PCOS patients. This up-regulation, along with the activation of WNT2/ß-Catenin pathway, was tightly associated with insulin resistance and estrogen deficiency, two hallmarks of PCOS. (ii) Overexpression of exogenous FZD3 in human granulosa cell COV434 impaired long-term FSH incubation-induced CYP19A1 transactivation and the recruitment of ß-Catenin onto CYP19A1 promoter, and subsequently compromised FSH-stimulated estrogen production. (iii) Conversely, inhibition of FZD3 expression exhibited a therapeutic effect on estrogen synthesis in PCOS CCs. Thus, excessive FZD3 expression in CCs may act as a brake on steroidogenic activation that is normally overcome by FSH stimulation. Future endeavor in this field should help to elucidate the complicated crosstalk between energy metabolism and endocrine cells through WNT/FZD signaling molecules.

Synergistic upregulation of NONO and PSPC1 regulates Sertoli cell response to MEHP via modulation of ALDH1A1 signaling.

Members of the Drosophila behavior/human splicing protein family, including splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1), are abundantly expressed in testicular Sertoli cells (SCs), but their roles remain obscure. Here, we show that treatment with mono-(2-ethylhexyl) phthalate (MEHP), a well-known SC toxicant, selectively stimulates the expression levels of NONO and PSPC1. Simultaneous inhibition of NONO and PSPC1 expression in SCs enhances MEHP-induced oxidative stress and potentiates SC death. Mechanistically, NONO and PSPC1 transcriptionally activate aldehyde dehydrogenase 1 (Aldh1a1), by synergistically binding to the distinct CCGGAGTC sequence in the Aldh1a1 promoter. Together, the NONO/PSPC1-ALDH1A1 cascade may serve as an indispensable defense mechanism against MEHP insult in SCs.

Plasma long non-coding RNA MALAT1 is associated with distant metastasis in patients with epithelial ovarian cancer.

Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a newly identified metastasis-associated long non-coding RNA. In a previous study, it was identified that plasma levels of MALAT1 were significantly increased in gastric cancer patients with metastasis compared with gastric cancer patients without metastasis and healthy control individuals. However, it is unclear whether plasma levels of MALAT1 may act as a biomarker for evaluating the development of metastasis in epithelial ovarian cancer (EOC). In the present study, groups that consisted of 47 patients with EOC and metastasis (EOC/DM), 47 patients with EOC without metastasis (EOC/NDM), and 47 healthy control (HC) individuals were established. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the level of plasma MALAT1 in these groups. The results showed that levels of plasma MALAT1 were significantly increased in the EOC/DM group compared with the EOC/NDM and HC groups (P<0.001). Receiver operating characteristic (ROC) analysis indicated that plasma MALAT1 yielded an area under the curve (AUC) of 0.820 [95% confidence interval (CI), 0.734-0.905; P<0.001], distinguishing between EOC/DM and EOC/NDM. ROC analysis also yielded an AUC of 0.884 (95% CI, 0.820-0.949; P<0.001), with 89.4% sensitivity and 72.3% specificity for distinguishing between EOC/DM and HC. Furthermore, multivariate analysis indicated that overexpression of MALAT1, differentiation (poor), tumor-node-metastasis stage (IV), lymph node metastasis (N3), peritoneal invasion (present) and higher serum carbohydrate antigen 125 levels were independent predictors of survival (hazard ratio, 3.322; P=0.028) in patients with EOC. Kaplan-Meier analysis revealed that patients with increased MALAT1 expression had a poorer disease-free survival time. In conclusion, the levels of plasma MALAT1 may act as a valuable biomarker for the diagnosis of metastasis.

Metastasis-associated protein 1 (MTA1) signaling in rheumatoid synovium: Regulation of inflammatory response and cytokine-mediated production of prostaglandin E2 (PGE2).

Abnormal perpetual inflammatory response and sequential cytokine-induced prostaglandin E2 (PGE2) play important roles in the pathogenesis of rheumatoid arthritis (RA). The underlying regulatory mechanism, however, remain largely unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), an important chromatin modifier that plays a critical role in transcriptional regulation by modifying DNA accessibility for cofactors, was upregulated in human rheumatoid synovial tissues. Furthermore, a knockdown of MTA1 by siRNA in the human fibroblast-like synovial cell line MH7A was found to impair the 4-hydroxynonenal (4-HNE)-induced transcriptional expression levels of certain proinflammatory cytokines including IL-1ß, TNF-α and IL-6. Moreover, endogenous MTA1 was required for the cytokines-induced PGE2 synthesis by rheumatoid synoviocytes. Collectively, the coordinated existence of MTA1 inside distinct cascade loops points to its indispensable role in the modulation of the integrated cytokine network along the pathogenesis of RA. Further exploration of the functional details of this master transcriptional regulator should be an attractive strategy to identify novel therapeutic target for RA and warrants execution.

MicroRNA-519 enhances HL60 human acute myeloid leukemia cell line proliferation by reducing the expression level of RNA-binding protein human antigen R.

Previous studies have demonstrated that microRNAs (miRs) are involved in cell apoptosis. However, the role of miR-519 in acute myeloid leukemia (AML) has yet to be elucidated. The present study identified the effects of miR­519 on HL60 human acute myeloid leukemia cell growth and apoptosis. The expression levels of miR­519 were examined in AML cells, as well as AML tissue samples. Furthermore, cell viability and apoptosis were examined in HL60 cells transfected with miR­519 mimics, miR­519 inhibitors or a negative control. In addition, the effects of human antigen R (HuR) on cell apoptosis were investigated using specific small interfering RNA targeting HuR. The results demonstrated that the expression levels of miR­519 were significantly increased in the AML cells and the tissue samples, suggesting that miR­519 may contribute to abnormal HL60 cell proliferation. Upregulation of miR­519 expression decreased HL60 cell viability and induced cell apoptosis. Furthermore, knockdown of HuR reduced cell migration and enhanced cell apoptosis. The results of the present study indicate that miR­519 may contribute to HL60 cell apoptosis by regulating the expression of HuR.