Increasing evidence shows that the anti-tumor functions of tumor-infiltrating T lymphocytes (TILs) were inhibited significantly, but the underlying mechanisms remain not fully understood. In this study, we found that 14-3-3ζ expression was up-regulated in hepatocellular carcinoma (HCC) cells and in TILs. TILs with 14-3-3ζ high-expression (14-3-3ζhigh) exhibited impaired activation (CD69), proliferation (Ki67) and anti-tumor functions compared to 14-3-3ζ low expression (14-3-3ζlow) TILs. Flow cytometry assay showed that compared with 14-3-3ζlow CD8+T cells, 14-3-3ζhigh ones exhibited higher frequency of exhausted phenotypes as measured by inhibitory receptors such as PD-1, TIM-3, LAG3, and CTLA-4. 14-3-3ζ overexpression inhibited the activity and proliferation of peripheral blood CD3+ T cells, deviated the differentiation of naive T cells from effector T cells to regulatory T cells. Moreover, we found that 14-3-3ζ expression levels in TILs correlated positively with those in HCC cells. Naive T cells co-cultured with HCC cells or the visible components of culture medium of HCC cells exhibited increased 14-3-3ζ expression. Stochastic optical reconstruction microscopy (STORM) and confocal assay showed that 14-3-3ζ-containing exosomes derived from HCC cells could be swallowed by T cells, suggesting that 14-3-3ζ might be transmitted from HCC cells to TILs at least partially through exosomes. In conclusion, our study for the first time demonstrated that 14-3-3ζ is up-regulated in and inhibited the anti-tumor functions of tumor-infiltrating T cells in HCC microenvironment and that 14-3-3ζ might be transmitted from HCC cells to T cells at least partially through exosomes.

/pdf/14-3-3z-delivered-by-hepatocellular-carcinoma-derived-3cvyo2g3ap.pdf

14-3-3ζ delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes.

Background: Circulating tumor cells (CTCs) are a burgeoning topic in cancer biomarker discovery research with minimal invasive blood draws. CTCs can be used as potential biomarkers for disease prognosis, early cancer diagnosis and pharmacodynamics. However, the extremely low abundance of CTCs limits their clinical utility because of technical challenges such as the isolation and subsequent detailed molecular and functional characterization of rare CTCs from patient blood samples. Methods: In this study, we present a novel density gradient centrifugation method employing biodegradable gelatin nanoparticles coated on silicon beads for the isolation, release, and downstream analysis of CTCs from colorectal and breast cancer patients. Results: Using clinical patient/spiked samples, we demonstrate that this method has significant CTC-capture efficiency (>80%) and purity (>85%), high CTC release efficiency (94%) and viability (92.5%). We also demonstrate the unparalleled robustness of our method in downstream CTC analyses such as the detection of PIK3CA mutations. Conclusion: The efficiency and versatility of the multifunctional density microbeads approach provides new opportunities for personalized cancer diagnostics and treatments.

Gelatin Nanoparticle-Coated Silicon Beads for Density-Selective Capture and Release of Heterogeneous Circulating Tumor Cells with High Purity.

Though long non-coding RNA LINC00858 (LINC00858) has been shown to be involved in tumours of other tissues, its involvement in colorectal cancer (CRC) is still unknown. We aimed to investigated expression and mechanism LINC00858 in human CRC. In this study, we firstly found that LINC00858 expression was significantly up-regulated in both CRC tissues and cell lines by both online data and RT-PCR assay. Then, clinical assay revealed that high LINC00858 expression was significantly associated with advanced clinical progression and poor prognosis. Multivariate analysis demonstrated that high LINC00858 expression was an independent poor prognostic factor for CRC patients. Moreover, lost-of-function assay indicated that knockdown of LINC00858 suppressed CRC cells proliferation, migration and invasion, and promoted apoptosis. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and western blot assays showed that LINC00858 functioned as competing endogenous RNA to repress miR-22-3p, which controlled its down-stream target YWHAZ. Then, we suggested that LINC00858 exerted its function through the miR-22-3p/YWHAZ axis. To our knowledge, this is the first report which showed the role of LINC00858 in the progression of CRC. Our findings indicated that LINC00858 played an important role in CRC, and may serve as a novel prognostic factor and therapeutic target.

Long non-coding RNA LINC00858 promotes cells proliferation, migration and invasion by acting as a ceRNA of miR-22-3p in colorectal cancer.

Background: As master regulator of embryonic morphogenesis, homeodomain-containing gene 10 (HOXC10) has been found to promote progression of human cancers and indicates poor survival outcome. However, the role of HOXC10 in lung adenocarcinoma still unclear. Methods: HOXC10 expression was evaluated in 63 primary lung adenocarcinoma tissues from our local hospital, and further systematically confirmed in lung cancer tissues from six GEO datasets (GSE19188, GSE31210, GSE10072, GSE7670, GSE32863, GSE30219) and Kaplan-Meier plotter database. The role of HOXC10 in lung cancer metastasis was further validated by cellular and molecular studies. Results: the expression of HOXC10 was significantly increased in human lung adenocarcinoma samples from Wuhu No.2 People’s Hospital, about 4.219 times compared with normal tissues, and significantly correlated with TNM stage, lymph node and distal metastasis. Upregulation of HOXC10 indicated a poor overall/relapse free survival of lung cancer patients from Wuhu No.2 People’s Hospital, GEO datasets and Kaplan-Meier plotter database, especially in patients with lung adenocarcinoma. Knockdown or ectopic expression assays confirmed that HOXC10 enhanced the phosphorylation of PI3K, regulated the expression of epithelial-to-mesenchymal transition (EMT) markers: MMP2/9, VCAM-1, vimentin and E-cadherin. Cellular study further confirmed that HOXC10 was required for migration, invasion and adhesion of lung cancer cells. Conclusion: These findings suggest that HOXC10 plays a pivotal role in the metastasis of human lung cancer and highlight its usefulness as a potential prognostic marker or therapeutic target in human lung adenocarcinoma.

/pdf/hoxc10-promotes-the-metastasis-of-human-lung-adenocarcinoma-ei0fwziqom.pdf

HOXC10 Promotes the Metastasis of Human Lung Adenocarcinoma and Indicates Poor Survival Outcome

In the current era of big data, the amount of data available is continuously increasing. Both the number and types of samples, or features, are on the rise. The mixing of distinct features often makes interpretation more difficult. However, separate analysis of individual types requires subsequent integration. A tensor is a useful framework to deal with distinct types of features in an integrated manner without mixing them. On the other hand, tensor data is not easy to obtain since it requires the measurements of huge numbers of combinations of distinct features; if there are m kinds of features, each of which has N dimensions, the number of measurements needed are as many as Nm, which is often too large to measure. In this paper, I propose a new method where a tensor is generated from individual features without combinatorial measurements, and the generated tensor was decomposed back to matrices, by which unsupervised feature extraction was performed. In order to demonstrate the usefulness of the proposed strategy, it was applied to synthetic data, as well as three omics datasets. It outperformed other matrix-based methodologies.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183933&type=printable

Tensor decomposition-based unsupervised feature extraction applied to matrix products for multi-view data processing.

Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson-Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.

/pdf/mir-22-targets-ywhaz-to-inhibit-metastasis-of-hepatocellular-oab5s1c3fv.pdf

miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.

The invention discloses an EpCAM/PSMA dual-antibody-based functionalized micro-fluidic chip as well as a preparation method and application thereof. The invention also discloses a method for capturingprostatic cancer CTCs by using the EpCAM/PSMA dual-antibody-based functionalized micro-fluidic chip as well as method for analyzing relevant molecular characteristic spectrum for the captured prostatic cancer CTCs. The relevant molecular phenotype is a prostatic cancer transfer relevant marker SChLAP1/PSA as well as targeting treatment response marker AR/PD-L1, so that a prostatic cancer CTCs molecular characteristic spectrum joint detection method and a detection kit can be constructed. The EpCAM/PSMA dual-antibody-based functionalized micro-fluidic chip is effective, high in specificity, high in sensitivity and high in accuracy, and also has clinical practical value, and the tetramolecular joint detection is used for the early warning of the transfer and reoccurrence and the curative effect evaluation in the prostatic cancer CTCs as well as improves the feasibility and credibility of the clinical use by virtue of the targeting treatment.

EpCAM/PSMA dual-antibody-based functionalized micro-fluidic chip as well as preparation method and application thereof

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miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.

EpCAM/PSMA dual-antibody-based functionalized micro-fluidic chip as well as preparation method and application thereof