Rare Earth Nanoprobes for Targeted Delineation of Triple Negative Breast Cancer and Enhancement of Radioimmunotherapy.

Radiotherapy demonstrates a synergistic effect with immunotherapy by inducing a transformation of "immune cold" tumors into "immune hot" tumors in triple negative breast cancer (TNBC). Nevertheless, the effectiveness of immunotherapy is constrained by low expression of tumor-exposed antigens, inadequate inflammation, and insufficient tumor infiltrating lymphocyte (TILs). To address this predicament, novel lutecium-based rare earth nanoparticles (RENPs) are synthesized with the aim of amplifying radiation effect and tumor immune response. The nanoprobe is characterized by neodymium-based down-conversion fluorescence, demonstrating robust photostability, biocompatibility, and targetability. The conjugation of RENPs with a CXCR4 targeted drug enables precise delineation of breast tumors using a near-infrared imaging system and improves radiation efficacy via lutetium-based radio-sensitizer in vivo. Furthermore, the study shows a notable enhancement of immune response through the induction of immunogenic cell death and recruitment of TILs, resulting in the inhibition of tumor progression both in vitro and in vivo models following the administration of nanoparticles. Hence, the novel multifunctional nanoprobes incorporating various lanthanide elements offer the potential for imaging-guided tumor delineation, radio-sensitization, and immune activation post-radiation, thus presenting an efficient radio-immunotherapeutic approach for TNBC.

Methylation of ESR1 promoter induced by SNAI2-DNMT3B complex promotes epithelial-mesenchymal transition and correlates with poor prognosis in ERα-positive breast cancers.

Estrogen receptor α (ERα) serves as an essential therapeutic predictor for breast cancer (BC) patients and is regulated by epigenetic modification. Abnormal methylation of cytosine phosphoric acid guanine islands in the estrogen receptor 1 (ESR1) gene promoter could silence or decrease ERα expression. In ERα-negative BC, we previously found snail family transcriptional repressor 2 (SNAI2), a zinc-finger transcriptional factor, recruited lysine-specific demethylase 1 to the promoter to transcriptionally suppress ERα expression by demethylating histone H3 lysine 4 dimethylation (H3K4me2). However, the role of SNAI2 in ERα-positive BC remains elusive. In this study, we observed a positive correlation between SNAI2 and ESR1 methylation, and SNAI2 promoted ESR1 methylation by recruiting DNA methyltransferase 3 beta (DNMT3B) rather than DNA methyltransferase 1 (DNMT1) in ERα-positive BC cells. Subsequent enrichment analysis illustrated that ESR1 methylation is strongly correlated with cell adhesion and junction. Knocking down DNMT3B could partially reverse SNAI2 overexpression-induced cell proliferation, migration, and invasion. Moreover, high DNMT3B expression predicted poor relapse-free survival and overall survival in ERα-positive BC patients. In conclusion, this study demonstrated the novel mechanisms of the ESR1 methylation mediated with the SNAI2/DNMT3B complex and enhanced awareness of ESR1 methylation's role in promoting epithelial-mesenchymal transition in BC.

RGD-functionalised melanin nanoparticles for intraoperative photoacoustic imaging-guided breast cancer surgery.

PURPOSE: Obtaining tumour-free margins is critical for avoiding re-excision and reducing local recurrence following breast-conserving surgery; however, it remains challenging. Imaging-guided surgery provides precise detection of residual lesions and assists surgical resection. Herein, we described water-soluble melanin nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast cancer photoacoustic imaging (PAI) and surgical navigation. METHODS: The cRGD-MNPs were synthesised and characterized for morphology, photoacoustic characteristics and stability. Tumour targeting and toxicity of cRGD-MNPs were determined by using either breast cancer cells, MDA-MB-231 tumour-bearing mice or the FVB/N-Tg (MMTV-PyVT) 634Mul/J mice model. PAI was used to locate the tumour and guide surgical resection in MDA-MB-231 tumour-bearing mice. RESULTS: The cRGD-MNPs exhibited excellent in vitro and in vivo tumour targeting with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site to that in the surrounding normal tissue was 3.2 ± 0.1, which was higher than that using MNPs (1.7 ± 0.3). Similarly, the PA signal in the spontaneous breast cancer increased ~ 2.5-fold at 2 h post-injection of cRGD-MNPs in MMTV-PyVT transgenic mice. Preoperative PAI assessed tumour volume and offered three-dimensional (3D) reconstruction images for accurate surgical planning. Surgical resection following real-time PAI showed high consistency with histopathological analysis. CONCLUSION: These results highlight that cRGD-MNP-mediated PAI provide a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs with fine PA properties have great potential for clinical translation.

Long non-coding RNA CCDC144NL-AS1 sponges miR-143-3p and regulates MAP3K7 by acting as a competing endogenous RNA in gastric cancer.

Gastric cancer (GC) has been one of the most leading cause of cancer-death worldwide. Long non-coding RNAs (lncRNAs) have been found to be related with the carcinogenesis and the development of various cancers, including GC. However, there are still many GC-related lncRNAs functional roles and molecular mechanisms that have not yet been clearly studied. Herein, we report lncRNA CCDC144NL-AS1, which has not been explored in GC, and it is markedly upregulated in GC tissues, which may serve as an independent predictor of poor prognosis. We found that CCDC144NL-AS1 expression was significantly positively associated with a larger tumor size and more pronounced lymph node metastasis. Through a series of in vivo and in vitro functional experiments, we observed that CCDC144NL-AS1 could facilitate cell proliferation, invasion and migration and inhibit cell apoptosis in GC. Further mechanism investigation revealed that CCDC144NL-AS1 acted as a competing endogenous RNA (ceRNA) for sponging miR-143-3p and upregulated the expression of its direct endogenous target MAP3K7 in GC. Taken together, our results elucidate the oncogenic roles of CCDC144NL-AS1/miR-143-3p/MAP3K7 axis in GC progression, providing inspiration for further understanding of the mechanism of GC and making CCDC144NL-AS1 as a potential novel diagnostic and therapeutic target for GC.

Long noncoding RNA TRPM2-AS acts as a microRNA sponge of miR-612 to promote gastric cancer progression and radioresistance.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis and are frequently dysregulated in cancers. Here, we identify a critical lncRNA TRPM2-AS which is aberrantly expressed in gastric cancer (GC) tissues by screening The Cancer Genome Atlas Program(TCGA) database of GC cohort, and its upregulation is clinically associated with advanced pathologic stages and poor prognosis in GC patients. Silencing TRPM2-AS inhibits the proliferation, metastasis and radioresistance of GC cell whereas ectopic expression of TRPM2-AS significantly improves the progression of GC cell in multiple experiments. Mechanistically, TRPM2-AS serves as a microRNA sponge or a competitive endogenous RNA (ceRNA) for tumor suppressive microRNA miR-612 and consequently modulates the derepression of IGF2BP1 and FOXM1. Moreover, induced upregulation of IGF2BP1 subsequently increases the expression of c-Myc and promotes GC cell progression. Meanwhile, TRPM2-AS promotes the radioreistance of GC cell through enhancing the expression of FOXM1 as well. Thus, our findings support a new regulatory axis between TRPM2-AS, miR-612, IGF2BP1, or FOXM1 which serve as crucial effectors in GC tumorigenesis and malignant development, suggesting a promising therapeutic and diagnostic direction for GC.

Downregulation of NUSAP1 suppresses cell proliferation, migration, and invasion via inhibiting mTORC1 signalling pathway in gastric cancer.

Gastric cancer (GC) is one of the most common causes of cancer-related death worldwide, and outstanding biomarkers for therapeutic targets or predicting GC survival are still lacking. Increasing evidence indicated that nucleolar and spindle associated protein 1 (NUSAP1) involved in regulating the progression of various cancers; however, its specific role in GC remained unclear. In this study, we found that NUSAP1 was upregulated in the GC tissues and cell lines via analysing data from The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO), qRT-PCR, and western blot assays. Patients with high NUSAP1 expression levels showed shorter free-progression survival (FPS), larger tumour size, and higher lymphatic metastasis rate compared with those with low NUSAP1 expression. Further functional experiments revealed knockdown of NUSAP1 could inhibit the growth, migration, and invasion of GC cells in vitro and vivo. Additionally, silencing NUSAP1 induced G0/G1 phase arrest, apoptosis, and suppressed the epithelial-mesenchymal transition (EMT) process. Finally, we performed gene set enrichment analysis (GSEA) and observed NUSAP1 was positive with mTORC1 signalling pathway, which was verified by the subsequent immunoblotting. In conclusion, our findings suggested that NUSAP1 contributed to GC progression and may act as a potential therapeutic target for GC. SIGNIFICANCE OF THE STUDY: Our results firstly illuminated that NUSAP1 expression was significantly upregulated in GC tissues and predicted poor FPS. Silencing it could attenuate GC progression via inhibiting mTORC1 signalling pathway. Hence, NUSAP1 may act as a promising therapy target for GC.

STRA6 exerts oncogenic role in gastric tumorigenesis by acting as a crucial target of miR-873.

BACKGROUND: Increasing evidence shows that stimulated by retinoic acid 6 (STRA6) participates in regulating multiple cancers. However, the biological roles of STRA6 in gastric cancer (GC) remain unknown. This study aimed to investigate the biological function of STRA6 and reveal the underlying mechanism of its dysregulation in GC. METHODS: The expression level of STRA6 was detected through quantitative real-time PCR and Western blot analysis. The effects of STRA6 on the proliferation of GC cells were studied through CCK-8 proliferation, colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays. The effects of STRA6 on migration and invasion were detected via wound healing and Transwell assays. Upstream miRNAs, which might regulate STRA6 expression, was predicted through bioinformatics analysis. Their interaction was further confirmed through dual-luciferase reporter assays and rescue experiments. RESULTS: STRA6 was up-regulated in GC and enhanced the proliferation and metastasis of GC cells in vitro and in vivo. STRA6 knockdown could inhibit the Wnt/ß-catenin signalling pathway. STRA6 was confirmed as an miR-873 target, which acted as a tumour suppressor in GC. Rescue assays showed that the repressing effect of miR-873 could be partially reversed by overexpressing STRA6. CONCLUSIONS: STRA6 is down-regulated by miR-873 and plays an oncogenic role by activating Wnt/ß-catenin signalling in GC.

Adenosquamous Carcinoma of the Stomach: A Population-based Study from the SEER Database.

Purpose: Gastric adenosquamous carcinoma (ASC) is a rare pathological type with poorly understood clinicopathological features. The purpose of this study is to identify the characteristics of gastric ASC patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database (2000 to 2014), patients with ASC (N=93) or adenocarcinoma (AC) (N=41794) of the stomach were included. The epidemiology, tumor features, treatment, and outcomes between these two groups were compared. Results: The incidences of ASC from 1983 to 2014 [annual percentage change (APC) = -3.5%, 95% confidence interval (CI) -4.9 to -2.1] and AC from 1973-2014 [APC = -1.8%, 95%CI -2.0 to -1.6] decreased over time. Compared to AC cases, patients with ASC were more likely to present poor differentiation (74.2% vs 52.4%) and later summary stage (distant: 46.2% vs 33.6%) or later T stage (T4: 15.1%% vs 9.0%). Besides, the proportion of patients with distant metastasis (33.3% vs 23.9%), and chemotherapy (44.1% vs 34.0%) in ASC group was higher. The Kaplan-Meier analyses showed ASC cases had worse overall survival (OS) (p=0.017) than that of AC after propensity score matching (PSM), but not the cancer-specific survival (CSS) (p=0.849). The further subgroup analyses suggested no statistical significance between gastric ASC patients and AC patients for CSS. The multivariate cox proportional hazard analyses indicated that patients with distant summary stage (HR=2.11, p=0.014), no surgery (HR=2.22, p=0.016), and no/unknown chemotherapy (HR=3.33, p<0.001) were associated with poor OS for ASC population alone. However, for CSS, only ASC cases with no/unknown chemotherapy (HR=2.22, p=0.018) indicated worse outcomes. Conclusions: Gastric ASC presented more aggressive clinicopathologic characteristics and poorer OS compared with AC. The localized/regional summary stages and undergoing surgery suggested favorable OS for gastric ASC patients. ASC cases receiving chemotherary showed both better OS and CSS.

Association of TP73-AS1 gene polymorphisms with the risk and survival of gastric cancer in a Chinese Han Population.

It was investigated that TP73-AS1(TP73 antisense RNA 1) could function as an oncogene in gastric cancer (GC). The expression and function of long noncoding RNAs (lncRNAs) could be impacted by single nucleotide polymorphisms (SNPs), which are related to cancer susceptibility and prognosis. This study was to reveal the association between lncRNAs TP73-AS1 polymorphisms (rs1181865 A > G, rs9800 G > C, rs3737589 A > G, rs2298222 G > A, rs7515164 C > A) and GC in 1000 GC cases and 1000 controls in a Chinese Han population. Rs3737589 G allele had significant associations with the increasing risk of GC (G vs. A: p = .005). Rs3737589 variant genotypes (AG + GG) were related to an increased risk of GC in the elder population (age ≥60), females, nonsmokers, nondrinkers, individuals living in urban, and individuals without family history of GC in stratified analyses. Rs3737589 variant genotypes (AG + GG) were related to the advanced depth of tumor invasion (T3 + T4). Besides, we found that GC patients with AG or GG genotype of rs3737589 had poorer overall survival (OS) than those with AA genotype (p < .05). Our findings showed that the lncRNA TP73-AS1 rs3737589 polymorphism might increase the risk of GC, and rs3737589 polymorphism could be a potential biomarker to predict the prognosis of GC patients.

miR-1254 inhibits cell proliferation, migration, and invasion by down-regulating Smurf1 in gastric cancer.

Gastric cancer (GC) is one of the most frequent malignancies, and increasing evidence supports the contribution of microRNA (miRNAs) to cancer progression. miR-1254 has been confirmed to participate in the regulation of various cancers, while the function of miR-1254 in GC remains unknown. In this study, we investigated the role of miR-1254 in GC. The expression of miR-1254 was detected in human GC specimens and cell lines by miRNA RT-PCR. The effects of miR-1254 on GC proliferation were determined by CCK-8 proliferation assays, colony formation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and cell-cycle assays. The ability of migration and invasion was examined by transwell and wound-healing assay. Dual Luciferase reporter assay was used to validate the interaction of miR-1254 with its target gene. The xenograft mouse models were conducted to investigate the effects of miR-1254 in vivo. The signaling pathways and epithelial-mesenchymal transition (EMT)-related proteins were detected with western blot. The results showed that miR-1254 inhibited the proliferation, migration and invasion in vitro and suppressed tumorigenesis in vivo. Smurf1 was shown to be the direct target of miR-1254. Overexpressing Smurf1 could partially counteract the effects caused by miR-1254. Similarly, the effects of the miR-1254-inhibitor were also rescued by Smurf1-shRNA. Furthermore, we found that miR-1254 inhibited EMT and decreased the PI3K/AKT signaling pathway through downregulating Smurf1. In summary, overexpression of miR-1254 could suppress proliferation, migration, invasion, and EMT via PI3K/AKT signaling pathways by downregulation of Smurf1 in GC, which suggests a potential therapeutic target for GC.

MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2.

BACKGROUND/AIMS: Gastric cancer (GC) is one of the most prevalent digestive malignancies. MicroRNAs (miRNAs) are involved in multiple cellular processes, including oncogenesis, and miR-592 itself participates in many malignancies; however, its role in GC remains unknown. In this study, we investigated the expression and molecular mechanisms of miR-592 in GC. METHODS: Quantitative real-time PCR and immunohistochemistry were performed to determine the expression of miR-592 and its putative targets in human tissues and cell lines. Proliferation, migration, and invasion were evaluated by Cell Counting Kit-8, population doubling time, colony formation, Transwell, and wound-healing assays in transfected GC cells in vitro. A dual-luciferase reporter assay was used to determine whether miR-592 could directly bind its target. A tumorigenesis assay was used to study whether miR-592 affected GC growth in vivo. Proteins involved in signaling pathways and the epithelial-mesenchymal transition (EMT) were detected with western blot. RESULTS: The ectopic expression of miR-592 promoted GC proliferation, migration, and invasion in vitro and facilitated tumorigenesis in vivo. Spry2 was a direct target of miR-592 and Spry2 overexpression partially counteracted the effects of miR-592. miR-592 induced the EMT and promoted its progression in GC via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2. CONCLUSIONS: Overexpression of miR-592 promotes GC proliferation, migration, and invasion and induces the EMT via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2, suggesting a potential therapeutic target for GC.