In addition to mutations or aberrant expression in the protein-coding genes, mutations and misregulation of noncoding RNAs, in particular long noncoding RNAs (lncRNA), appear to play major roles in cancer. Genome-wide association studies of tumor samples have identified a large number of lncRNAs associated with various types of cancer. Alterations in lncRNA expression and their mutations promote tumorigenesis and metastasis. LncRNAs may exhibit tumor-suppressive and -promoting (oncogenic) functions. Because of their genome-wide expression patterns in a variety of tissues and their tissue-specific expression characteristics, lncRNAs hold strong promise as novel biomarkers and therapeutic targets for cancer. In this article, we have reviewed the emerging functions and association of lncRNAs in different types of cancer and discussed their potential implications in cancer diagnosis and therapy. Cancer Res; 77(15); 3965-81. ©2017 AACR.

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Long Noncoding RNA and Cancer: A New Paradigm.

Inflammation is a fundamental innate immune response to perturbed tissue homeostasis. Chronic inflammatory processes affect all stages of tumour development as well as therapy. In this Review, we outline the principal cellular and molecular pathways that coordinate the tumour-promoting and tumour-antagonizing effects of inflammation and we discuss the crosstalk between cancer development and inflammatory processes. In addition, we discuss the recently suggested role of commensal microorganisms in inflammation-induced cancer and we propose that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment.

Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms.

Competing endogenous RNAs (ceRNAs) are transcripts that can regulate each other at post-transcription level by competing for shared miRNAs. CeRNA networks link the function of protein-coding mRNAs with that of non-coding RNAs such as microRNA, long non-coding RNA, pseudogenic RNA and circular RNA. Given that any transcripts harbouring miRNA response element can theoretically function as ceRNAs, they may represent a widespread form of post-transcriptional regulation of gene expression in both physiology and pathology. CeRNA activity is influenced by multiple factors such as the abundance and subcellular localisation of ceRNA components, binding affinity of miRNAs to their sponges, RNA editing, RNA secondary structures and RNA-binding proteins. Aberrations in these factors may deregulate ceRNA networks and thus lead to human diseases including cancer. In this review, we introduce the mechanisms and molecular bases of ceRNA networks, discuss their roles in the pathogenesis of cancer as well as methods of predicting and validating ceRNA interplay. At last, we discuss the limitations of current ceRNA theory, propose possible directions and envision the possibilities of ceRNAs as diagnostic biomarkers or therapeutic targets.

https://jmg.bmj.com/content/jmedgenet/52/10/710.full.pdf

ceRNA in cancer: possible functions and clinical implications

Immuno-oncology is an emerging field that has revolutionized cancer treatment Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies

Natural killer cells and other innate lymphoid cells in cancer.

Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.24486

Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.

Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC) Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC

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The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion.

Location-associated long noncoding RNA (lncRNA) was reported to interact with target protein via a cis-regulatory process especially for the Flank10kb class lncRNA. Based on this theory, we aimed to explore the regulatory mechanisms of Linc00974 and KRT19 (an lncRNA beyond the Flank10kb class with protein) when we first confirmed the aberrant expression in hepatocellular carcinoma in a previous study. Knockdown of Linc00974 resulted in an inhibition of cell proliferation and invasion with an activation of apoptosis and cell cycle arrest in vitro, which was also validated by a subcutaneous and tail vein/intraperitoneal injection xenotransplantation model in vivo. We further investigated the interaction pattern of Linc00974 and KRT19. MiR-642 was identified, by acting as the competing endogenous RNA in regulating Linc00974 and KRT19. Linc00974 was increased owing to an abnormal hypomethylation promoter, which induced the upregulation of KRT19 via ceRNA interaction, resulting in the activation of the Notch and TGF-β pathways as detected by cDNA microarray. We also discovered Linc00974F-1 stably expressed in the plasma. By the combined analysis of Linc00974F-1 with CYFRA21-1, we found that these joint indicators predicted growth and metastasis of tumor in HCC patients. In conclusion, the combination of Linc00974 and KRT19 may be novel indices for clinical diagnosis of tumor growth and metastasis in HCC, while Linc00974 may become a potential therapeutic target for the prevention of HCC progression.

/pdf/a-novel-biomarker-linc00974-interacting-with-krt19-promotes-5ay313k1b2.pdf

A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma

It has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC). The expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model. Our results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22. In this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.

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IL-22 is related to development of human colon cancer by activation of STAT3

// Junwei Tang 1, 2, * , Runqiu Jiang 1, 2, * , Lei Deng 1, 2 , Xudong Zhang 1, 2 , Ke Wang 1, 2 , Beicheng Sun 1, 2 1 Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, P.R.China 2 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R.China * These authors have contributed equally to this work Correspondence to: Beicheng Sun, e-mail: sunbc@njmu.edu.cn Ke Wang, e-mail: lancetwk@163.com Keywords: plasma, lncRNA, microarray, risk score function, ROC curve Received: November 09, 2014      Accepted: December 16, 2014      Published: February 25, 2015 ABSTRACT BACKGROUND & AIMS Alpha Fetal Protein (AFP) was one of the traditional biomarker for diagnosis of Hepatocellular carcinoma (HCC) clinically, however, with the low specificity of AFP, the early diagnosis or the metastasis prediction of HCC is inferior. A new, minimally invasive and more specificity biomarker for the diagnosis or metastasis prediction of HCC are necessary. METHODS In this study, we applied an lncRNA microarray to screen the potential biomarker for HCC. The multi-stage validation and risk score formula detection was used for validation. RESULTS We discovered three lncRNA, RP11–160H22.5, XLOC_014172 and LOC149086, which were up-regulated in HCC comparing with the cancer-free controls with the merged area under curve (AUC) in training set and validation set of 0.999 and 0.896. Furthermore, XLOC_014172 and LOC149086 was confirmed highly increased in metastasis HCC patients with the merged AUC in training set and validation set of 0.900 and 0.934. Besides, most patients presented a decreased level of the three lncRNAs after operation, while the patients with secondary increased level might be associated with tumor hematogenous metastasis. CONCLUSIONS RP11–160H22.5, XLOC_014172 and LOC149086 might be the potential biomarker for the tumorigenesis prediction and XLOC_014172 and LOC149086 for metastasis prediction in the future.

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Lei Deng

Papers

Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.

The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion.

A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma

IL-22 is related to development of human colon cancer by activation of STAT3

Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma