Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis.

Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.

An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence.

The poor survival and recurrence rate in gastric adenocarcinoma highlights the need for cancer gene discovery. Towards this end, we globally assessed the expression of an emerging class of small non-coding RNAs, called PIWI-interacting RNAs (piRNAs). We analysed the transcriptomes of 358 non-malignant stomach tissue and gastric adenocarcinoma samples, and found that nearly half of the expressed piRNAs were overexpressed in tumours. Our gastric piRNA atlas showed that most piRNAs were embedded in protein-coding sequences rather than known piRNA clusters. Furthermore, we identified a three-piRNA signature associated with recurrence-free survival. In this proof-of-principle study, we demonstrate the potential clinical utility of piRNAs in gastric cancer.

Epithelial tumor suppressor ELF3 is a lineage-specific amplified oncogene in lung adenocarcinoma.

Gene function in cancer is often cell type-specific. The epithelial cell-specific transcription factor ELF3 is a documented tumor suppressor in many epithelial tumors yet displays oncogenic properties in others. Here, we show that ELF3 is an oncogene in the adenocarcinoma subtype of lung cancer (LUAD), providing genetic, functional, and clinical evidence of subtype specificity. We discover a region of focal amplification at chromosome 1q32.1 encompassing the ELF3 locus in LUAD which is absent in the squamous subtype. Gene dosage and promoter hypomethylation affect the locus in up to 80% of LUAD analyzed. ELF3 expression was required for tumor growth and a pan-cancer expression network analysis supports its subtype and tissue specificity. We further show that ELF3 displays strong prognostic value in LUAD but not LUSC. We conclude that, contrary to many other tumors of epithelial origin, ELF3 is an oncogene and putative therapeutic target in LUAD.

MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis.

Ubiquilin (UBQLN) proteins are adaptors thought to link ubiquitinated proteins to the proteasome. However, our lab has recently reported a previously unappreciated role for loss of UBQLN in lung cancer progression. In fact, UBQLN genes are lost in over 50% of lung cancer samples examined. However, a reason for the loss of UBQLN has not been proposed, nor has a selective pressure that could lead to deletion of UBQLN been reported. Diesel Exhaust Particles (DEP) are a major concern in the large cities of developing nations and DEP exposed populations are at an increased risk of developing a number of illnesses, including lung cancer. A connection between DEP and UBQLN has never been examined. In the present study, we determined the effect of DEP on lung cell lines and were interested to determine if UBQLN proteins could potentially play a protective role following treatment with DEP. Interestingly, we found that DEP treated cells have increased expression of UBQLN proteins. In fact, over-expression of UBQLN was capable of protecting cells from DEP toxicity. To investigate the mechanism by which DEP leads to increased UBQLN protein levels, we identified and interrogated microRNAs that were predicted to regulate UBQLN mRNA. We found that DEP decreases the oncogenic microRNA, MIR155. Further, we showed that MIR155 regulates the mRNA of UBQLN1 and UBQLN2 in cells, such that increased MIR155 expression increased cell invasion, migration, wound formation and clonogenicity in UBQLN-loss dependent manner. This is the first report of an environmental carcinogen regulating expression of UBQLN proteins. We show that exposure of cells to DEP causes an increase in UBQLN levels and that MIR155 regulates mRNA of UBQLN. Thus, we propose that DEP-induced repression of MIR155 leads to increased UBQLN levels, which in turn may be a selective pressure on lung cells to lose UBQLN1.

HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer.

OBJECTIVES: As HPV-induced cases of oral malignancy increase, it is important to understand the molecular differences between HPV positive and negative head and neck squamous cell carcinoma (HNSCC). PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs aberrantly expressed in cancer. We analyzed global piRNA expression patterns to define the HNSCC piRNA transcriptome and assess whether HPV infection status associates with changes in piRNA levels. MATERIALS AND METHODS: A total of 498 HNSCC small RNA sequencing libraries were acquired from the Cancer Genomics Hub (cgHUB) Data Repository and a custom sequence analysis pipeline was developed to deduce piRNA expression from raw sequencing data. Expression matrices were aligned to clinicopathological features in order to analyze piRNA expression patterns across different HNSCC groups. The association of a piRNA signature with HPV-positive patient survival was evaluated using a Cox proportional hazard model. RESULTS: Analysis of piRNA levels between HNSCC and non-malignant tissues revealed distinct expression patterns, with 87 piRNAs exclusively expressed in tumor samples. HPV infection status affected the expression of 41 of these piRNAs. Eleven (26.8%) piRNAs were significantly downregulated in HPV16/18 tumors compared to other HPV types. Remarkably, expression of a combination of five-piRNAs in HPV-positive HNSCC tumors was associated with worse overall survival. CONCLUSION: The expression of specific piRNAs is deregulated in HNSCC, and changes with both HPV status and type. Importantly, a five-piRNA signature is able to delineate a subset of HPV-positive HNSCC patients with poor outcome, highlighting the potential utility of piRNAs in patient management.

Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma.

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.