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Pancreatic cancer (PC) mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. Long non-coding RNAs (lncRNAs) are well known as a class of transcripts involved in cancer occurrence and progression. The process of epithelial to a mesenchymal (EMT) phenotype in tumor cell increases their migratory and invasive properties, resulting in facilitating metastasis. Here, we reanalyzed RNA-seq data from the TCGA PC database and identified that ENSG00000254041.1 increasingly expressed in samples with elevated EMT signature score. Then, the evaluated expression and prognostic significance of ENSG00000254041.1 were verified in our cohort. Meanwhile, multivariate analysis suggested that ENSG00000254041.1 was independent factors for predicting the prognosis of PC, apart from advanced stage (III/IV). Moreover, functional assay revealed that knock down of ENSG00000254041.1 significantly decreased proliferation, invasion and chemoresistance of PC cells (SW1990 and BxPC-3), while overexpression of ENSG00000254041.1 in PC cells (Panc-1) resulted in the opposite effects. Western blot showed that knockdown of ENSG00000254041.1 expression in PC cells caused a significant downregulation of vimentin, Snail and SOX4, and upregulation of E-cadherin; also, ENSG00000254041.1 overexpression in PC cells resulted in opposite effects. In conclusion, these findings indicated that ENSG00000254041.1 promotes PC progression, and might provide a potential biomarker for predicting the prognosis of PC.

Simple Summary While modulating gut microbiota using dietary intervention with natural nutrients has proven to be effective in improving the response rate of immune checkpoint inhibitors (ICIs), the underpinning mechanism is poorly understood. This work demonstrates that the oral administration of ultrafine jujube powder (JP) let to a significant alteration of gut microbiota, an increased abundance of Clostridiales, including Ruminococcaceae and Lachnospiraceae, an elevated SCFA production, an intensified infiltration of CD8+ T cells to the tumor microenvironment, and a greatly improved response of anti-PD-L1 treatment against murine colon adenocarcinoma. Moreover, the size of the JP particles had a significant impact on the abovementioned attributes. The present study demonstrates that dietary intervention with nutrients is highly effective in modulating the gut microbiota for an improved immune checkpoint blockage therapy. Abstract Whereas dietary intervention with natural nutrients plays an important role in activating the immune response and holds unprecedented application potential, the underpinning mechanism is poorly understood. The present work was dedicated to comprehensively examine the effects of ultrafine jujube powder (JP) on the gut microbiota and, consequentially, the effects associated with the response rate to anti-PD-L1 treatment against murine colon adenocarcinoma. A murine colon adenocarcinoma model with anti-PD-L1 immunotherapy was established to evaluate how dietary interventions affect the microbiota. In vitro and in vivo experiments confirmed the role of SCFAs in the immune response. Oral administration of JP greatly improves the response of anti-PD-L1 treatment against murine colon adenocarcinoma. Such an improvement is associated with the alteration of gut microbiota which leads to an increased abundance of Clostridiales, including Ruminococcaceae and Lachnospiraceae, an elevated SCFA production, and an intensified infiltration of CD8+ T cells to the tumor microenvironment. This work demonstrates that JP is particularly effective in modulating the gut microbiota for an improved immune checkpoint blockage therapy by boosting cytotoxic CD8+ T cells in tumor-infiltrating lymphocytes. The experimental findings of the present study are helpful for the development of dietary intervention methods for cancer immunotherapy using natural nutrients.

Low response rates to certain tumor types remain a major challenge for immune checkpoint blockade therapy. In this study, we first conducted an integrated biomarker evaluation of bladder cancer patients from confirmatory cohorts (IMvigor210) and found that no significant differences exist between sexes before acceptance of anti-PD-L1 treatment, whereas male patients showed a better response. Thus, we then focused on sex-related changes post anti-PD-L1 treatment and found no obvious impact on the gut microbiota in male mice but a significant decrease in the sex hormone levels. Further, castration dramatically enhanced the antitumor efficacy against murine colon adenocarcinoma in male mice. Moreover, a narrow-spectrum antibiotic, colistin was innovatively used for deregulation of testosterone levels to enhance the immunotherapy efficiency in male mice. These findings indicate that the impact on the sex hormone levels in males may contribute to the sexual dimorphism in response and provide a promising way to enhance immunotherapy efficiency.

BACKGROUND Hepatocellular carcinoma (HCC) accounts for one of the most prevalent tumor types in the world. The MAP kinase-interacting kinase 1 (MNK1) functions downstream of MAP kinases such as p38 and ERK, and its potential role in cancer development is being uncovered. The aim of this study was to investigate the expression and function of MNK1 in HCC. MATERIAL AND METHODS Immunohistochemical staining and quantitative PCR were performed to explore the expression of MNK1 in both HCC tissues and adjacent normal liver tissues. Chi-square test, univariate analysis, and multivariate analysis were conducted to statistically evaluate clinical significance of MNK1 in HCC. Proliferation, migration, and invasion capacities of HCC cells were assessed after overexpressing or silencing MNK1. RESULTS Both the RNA and protein levels of MNK1 were upregulated in HCC tissues compared to normal liver tissues. High expression of MNK1 was correlated with advanced tumor stage and poor overall survival. Moreover, MNK1 was identified as a novel independent prognostic factor for HCC patients. Cellular studies showed that MNK1 can enhance the proliferation, migration, and invasion capacities of HCC cells, thereby promoting tumor progression. CONCLUSIONS High expression of MNK1 is frequent in HCC tissues, which promotes tumor proliferation and invasion, and is correlated with a poor overall survival. Targeting MNK1 may be a novel direction for the drug development of HCC therapy.

Cyclophosphamide (CTX) is widely applied in cancer treatment. However, the outcome is often compromised by lymphopenia, myelosuppression, and gut dysbiosis. Here, we used jujube powder to enhance CTX efficiency through nurturing gut microbiota in order to facilitate favorable metabolisms. It was observed that the oral administration of jujube powder enriched CD8+ T cells in mouse MC38 colon tumor microenvironment and increased the diversity of gut microbiota and the abundance of Bifidobacteriales, which is helpful to the production of butyrate in the cecum content. The application of jujube powder also stimulated the production of white blood cells, especially CD8+ T cells in peripheral and bone marrow, while inhibiting the growth of eosinophils in peripheral blood and the production of IL-7 and GM-CSF in serum. All these are conductive to the significant inhibition of the tumor growth, suggesting the high potential of nurturing gut microbiota with natural products for improving the efficiency of chemotherapy.

Long non-coding RNAs (lncRNAs) have been shown to play a significant role in the progression of many cancers, including pancreatic cancer (PC). However, the biological function and regulatory mechanisms of lncRNAs in PC remains largely unclear. The aim of this study was to identify and evaluate the potential functions of lncRNAs in PC and reveal the underlying mechanisms of their effects. Screening of published microarray data (GEO accession Nos. {"type":"entrez-geo","attrs":{"text":"GSE16515","term_id":"16515"}}GSE16515 and {"type":"entrez-geo","attrs":{"text":"GSE32688","term_id":"32688"}}GSE32688), revealed lncRNA AFAP1-AS1 to be one of the most upregulated lncRNAs in PC tissues. High expression of AFAP1-AS1 was correlated with advanced stages, tumor size and lymph node metastasis, as well as with poorer overall survival in patients with PC. Functionally, knockdown of AFAP1-AS1 by transfection with siRNA inhibited the proliferative and invasive capacities of PaCa-2 and SW1990 PC cells, promoted apoptosis of PC cells in vitro, and impaired in-vivo tumorigenicity. In particular, it was hypothesized that AFAP1-AS1 may act as a competitive endogenous RNA (ceRNA), effectively becoming a sink for miR-133a whose expression was found to be downregulated in PC tissues and cell lines, and which was negatively correlated with the expression of AFAP1-AS1. We also found that the IGF1R oncogene which is an important regulator of MEK/ERK signaling pathway, was positively regulated by AFAP1-AS1 through ameliorating miR-133a-mediated IGF1R repression in PC tissues. Moreover, we demonstrated that knockdown of IGF1R by transfection with si-IGF1R suppressed cell proliferation, invasion and migration of PaCa-2 and SW1990 PC cells, suggesting that IGF1R may function as an oncogene in PC cells. Further investigations revealed that miR-133a reversed the biological effects of AFAP1-AS1 on PC cells. Collectively, the findings provide new evidence that AFAP1-AS1 could regulate the progression of pancreatic cancer by acting as a ceRNA, and suggest it has potential for use as both a biomarker for the early detection PC and for the development of individualized therapies for PC.