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Hepatocellular carcinoma (HCC) is the fifth most common malignancy caused by environmental and genetic factors. MicroRNAs (miRNAs) are a class of short non-coding RNAs with posttranscriptional regulatory functions. They participate in diverse biological pathways and function as gene regulators. Genetic polymorphisms in 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding, with consequences on regulation of target genes thereby affecting the individual's cancer risk. We have previously predicted polymorphisms falling in miRNA-binding regions of cancer genes. We selected an insertion/deletion (Indel) polymorphism (rs3783553) in the 3' UTR of interleukin (IL)-1alpha (IL1A) for a case-control study in a Chinese population. With samples from 403 HCC patients and 434 healthy control individuals, strong evidence of association was observed for the variant homozygote. This association was validated in a second independent case-control study with 1074 HCC patients and 1239 healthy control individuals (odds ratio = 0.62; 95% confidence interval = 0.49-0.78). We further show that the 'TTCA' insertion allele for rs3783553 disrupts a binding site for miR-122 and miR-378, thereby increasing transcription of IL-1alpha in vitro and in vivo. These findings suggest that functional polymorphism rs3783553 in IL1A could contribute to HCC susceptibility. Considering IL-1alpha affects not only various phases of the malignant process, such as carcinogenesis, tumor growth and invasiveness, but also patterns of interactions between malignant cells and the host's immune system, our results indicated that IL-1alpha may be a promising target for immunotherapy, early diagnosis and intervention of HCC.

PIWI interacting RNAs (piRNAs) are highly expressed in germline cells and are involved in maintaining genome integrity by silencing transposons. These are also involved in DNA/histone methylation and gene expression regulation in somatic cells of invertebrates. The functions of piRNAs in somatic cells of vertebrates, however, remain elusive. We found that snoRNA-derived and C (C′)/D′ (D)-box conserved piRNAs are abundant in human CD4 primary T-lymphocytes. piRNA (piR30840) significantly downregulated interleukin-4 (IL-4) via sequence complementarity binding to pre-mRNA intron, which subsequently inhibited the development of Th2 T-lymphocytes. Piwil4 and Ago4 are associated with this piRNA, and this complex further interacts with Trf4-Air2-Mtr4 Polyadenylation (TRAMP) complex, which leads to the decay of targeted pre-mRNA through nuclear exosomes. Taken together, we demonstrate a novel piRNA mechanism in regulating gene expression in highly differentiated somatic cells and a possible novel target for allergy therapeutics.

PIWI-interacting RNA (piRNA) silences the transposons in germlines or induces epigenetic modifications in the invertebrates. However, its function in the mammalian somatic cells remains unknown. Here we demonstrate that a piRNA derived from Growth Arrest Specific 5, a tumor-suppressive long non-coding RNA, potently upregulates the transcription of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a proapoptotic protein, by inducing H3K4 methylation/H3K27 demethylation. Interestingly, the PIWIL1/4 proteins, which bind with this piRNA, directly interact with WDR5, resulting in a site-specific recruitment of the hCOMPASS-like complexes containing at least MLL3 and UTX (KDM6A). We have indicated a novel pathway for piRNAs to specially activate gene expression. Given that MLL3 or UTX are frequently mutated in various tumors, the piRNA/MLL3/UTX complex mediates the induction of TRAIL, and consequently leads to the inhibition of tumor growth.

Since entering the immunological stage several decades ago, regulatory T cell biology has been realized as fundamentally important in the prevention of autoimmune conditions, induction of transplant tolerance and the immune response to cancer. The role of regulatory T cells in tumor immunobiology is still being elucidated. Currently, regulatory T cells are implicated in the dampening of antitumor T-cell responses both through direct and indirect means. A number of investigators have demonstrated that regulatory T cell density and location may serve as independent prognostic factors in several types of cancer and are alternately detrimental or beneficial to patient survival. In this article, we will review the characteristics and functional phenotype of classical regulatory T cells, describe their distribution and quantification in tumor-bearing hosts and summarize recent studies investigating the prognostic significance of regulatory T cell number and locality in various cancers.

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The TATA box represents one of the most prevalent core promoters where the pre-initiation complexes (PICs) for gene transcription are assembled. This assembly is crucial for transcription initiation and well regulated. Here we show that some cellular microRNAs (miRNAs) are associated with RNA polymerase II (Pol II) and TATA box-binding protein (TBP) in human peripheral blood mononuclear cells (PBMCs). Among them, let-7i sequence specifically binds to the TATA-box motif of interleukin-2 (IL-2) gene and elevates IL-2 mRNA and protein production in CD4 + T-lymphocytes in vitro and in vivo. Through direct interaction with the TATA-box motif, let-7i facilitates the PIC assembly and transcription initiation of IL-2 promoter. Several other cellular miRNAs, such as mir-138, mir-92a or mir-181d, also enhance the promoter activities via binding to the TATA-box motifs of insulin, calcitonin or c-myc, respectively. In agreement with the finding that an HIV-1-encoded miRNA could enhance viral replication through targeting the viral promoter TATA-box motif, our data demonstrate that the interaction with core transcription machinery is a novel mechanism for miRNAs to regulate gene expression.

Maternal immune system tolerance to the semiallogeneic fetus is essential for a successful pregnancy; however, the mechanisms underlying this immunotolerance have not been fully elucidated. Here, we demonstrate that myeloid-derived suppressor cells play an important role in maintaining feto-maternal tolerance. A significant expansion of granulocytic myeloid-derived suppressor cells was observed in multiple immune organs and decidual tissues from pregnant mice. Pregnancy-derived granulocytic myeloid-derived suppressor cells suppressed T cell responses in a reactive oxygen species-dependent manner and required direct cell-cell contact. Mechanistic studies showed that progesterone facilitated differentiation and activation of granulocytic myeloid-derived suppressor cells, mediated through STAT3 signaling. The STAT3 inhibitor JSI-124 and a specific short hairpin RNA completely abrogated the effects of progesterone on granulocytic myeloid-derived suppressor cells. More importantly, granulocytic myeloid-derived suppressor cell depletion dramatically enhanced the abortion rate in normal pregnant mice, whereas adoptive transfer of granulocytic myeloid-derived suppressor cells clearly reduced the abortion rate in the CBA/J X DBA/2J mouse model of spontaneous abortion. These observations collectively demonstrate that granulocytic myeloid-derived suppressor cells play an essential role in the maintenance of fetal immunotolerance in mice. Furthermore, our study supports the notion that in addition to their well-recognized roles under pathologic conditions, myeloid-derived suppressor cells perform important functions under certain physiologic circumstances.