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Brenda C. Minatel
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.12 - Expanding the Lung Small RNA Transcriptome: Discovery of Unannotated microRNAs with Roles in Development and Tumourigenesis (ID 9100)
15:45 - 17:30 | Presenting Author(s): Brenda C. Minatel
- Abstract
- Presentation
Background:
MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.
Method:
A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.
Result:
Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.
Conclusion:
Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-006 - Arsenic Promotes Persistent Alterations in the Lung PiRNA Transcriptome to Target Epigenetic Pathways (ID 9567)
09:30 - 16:00 | Author(s): Brenda C. Minatel
- Abstract
Background:
Chronic exposure to arsenic leads to the onset of different diseases, including lung cancer. Arsenic-induced lung tumors have been associated with a high-frequency of lung squamous-cell carcinomas among never smokers (a rare epidemiological pattern), suggesting a unique underlying biology. Epigenetic alterations are known to play a role in this process; however, detailed mechanisms are not yet fully elucidated. Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs (sncRNAs), play a key role in epigenetic regulation and maintenance of genome integrity. Here, we examine the impact of different arsenic species in the human piRNA transcriptome, using lung cell models mirroring chronic, low dose exposure. We also investigate the interaction network of deregulated piRNAs and identified biological pathways potentially affected.
Method:
One normal lung (HBEC) and two lung cancer cell lines: A459 (adenocarcinoma) and H520 (squamous-cell carcinoma) were grown in 10 ppm of sodium arsenite (AsIII) or arsenate (AsV) for six passages. Total RNA was extracted at different time points and sequenced. piRNA expression was deduced using our custom sncRNA analysis pipeline, which interrogates >23K piRNA-encoding human loci. piRNA/DNA binding prediction was performed using two different algorithms (miRanda/ThermoBLAST). Network analysis was performed using Partek Pathways.
Result:
Overall, 691 piRNAs were expressed. Persistent changes in piRNA expression over time were identified, with specific patterns associated with the different arsenic species. In HBECs (non-malignant lung tissue), 14 piRNAs were persistently upregulated and 16 downregulated in response to AsIII. Similarly, 6 were up- and 11 downregulated when the same cells were exposed to AsV. Only 1 piRNA, DQ598008, was commonly upregulated in response to both arsenic species, while 4 piRNAs were commonly downregulated. Lung cancer cell lines follow the same arsenic species-specific trends, with a high subtype-specificity indicating these species maintain a role during lung tumor development. Remarkably, we found an enrichment of genes associated with methyltransferase activities predicted to be targeted by piRNAs altered by AsIII (a biologically-relevant form of arsenic), evidencing their role in arsenic-related carcinogenic mechanisms.
Conclusion:
Arsenic induces persistent alterations in the lung sncRNA transcriptome, particularly piRNAs, impacting pathways linked to epigenetic regulation. Together, these results provide insights into sncRNA-related mechanisms in arsenic-induced lung carcinogenesis. Moreover, different arsenic species induce distinct alteration patterns, highlighting the relevance of the source of exposure. piRNAs, as with other sncRNAs, are stable in biofluids, circulating tumour cells, and archival clinical materials. Therefore, piRNAs hold great promise as potential exposure and monitoring biomarkers for arsenic-related health effects.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-090 - Hypoxia-Induced Modifications of the Small Non-Coding RNA Transcriptome Delineates Risk of Recurrence in Early-Stage Lung Adenocarcinoma (ID 8400)
09:30 - 16:00 | Author(s): Brenda C. Minatel
- Abstract
Background:
Hypoxia is central to neoplastic diseases. It has been associated with reduced survival in several tumor types, including NSCLC. A spectrum of poor outcome suggests a multifactorial modulation of the hypoxic response. Piwi-interacting RNAs (piRNAs) are small non-coding RNAs (sncRNAs) with a pivotal role in genomic stability and epigenetic regulation of gene expression. Changes in piRNA expression have been recently found to be deregulated during tumor progression, and responsive to tumor microenvironment conditions. Here, we investigate if hypoxia alters the piRNA transcriptome in human lungs, and assessed whether these alterations are indicative of outcome in patients with hypoxic lung tumours.
Method:
Tumors from lung and other six organs (TCGA) were classified according to their oxygenation state using signatures derived from established hypoxia-associated gene expression changes. By investigating >3000 piRNA transcriptomes, we generated a baseline of hypoxia-related changes which were further validated in a panel of cell lines exposed to hypoxia in vitro (16h at 1% O~2~). In lung tumors (n=1,018), we identified the most robust hypoxia-related changes between hypoxic and non-hypoxic groups by including piRNAs that: 1) ≥ 10 RPKM median expression, 2) > 2-fold change in median expression, and 3) a significant p value following a Mann-Whitney U test. A piRNA-based score (piSco) was generated by grouping HR-piRNAs expression, weighted by coefficients from a Cox proportional hazard model.
Result:
Overall, piRNA expression is selectively deregulated by hypoxia. In vitro tumour models recapitulate HR-piRNAs expression patterns. Seventy-one HR-piRNAs were identified, showing statistically significant differences in expression between hypoxic and non-hypoxic tumours. Of these, 13 were exclusively deregulated in NSCLC tumors, showing a remarkable subtype specificity between adenocarcinomas and squamous cell carcinomas. We next investigated if the HR-piRNA based score (piSco) was associated with NSCLC patient outcome. We found that piSco classify patients with hypoxic lung LUAD and LUSC as low or high risk of RFS. Remarkably, piSco was also able to classify Stage I LUAD patients into the same categories above (p = 0.0051).
Conclusion:
This study reveals the influence of the tumour microenvironment on DNA-level regulatory mechanisms with important implications for predicting recurrence in patients with hypoxic lung tumours. Our data encourage further exploration of HR-piRNAs as clinical tools for evaluating the likelihood of tumour recurrence, and as a mean to identify patients that would most benefit from adjuvant therapies and/or therapies designed to target hypoxic tumour cells.
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P3.02-094 - Identification of Oncofetal piRNAs in Lung (ID 9107)
09:30 - 16:00 | Presenting Author(s): Brenda C. Minatel
- Abstract
Background:
PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs (distinct from microRNAs) that recognize complementary DNA sequences in the nucleus. Their primary functions involve epigenetic control of gene transcription and maintenance of genomic stability through repression of mobile elements. Recent observations of cancer type specific aberrant expression have raised the possibility of a role for piRNAs in lung cancer. Here we characterize piRNA transcriptomes of fetal, adult and tumour lung tissue to identify fetal piRNA genes that are silenced in normal adult lung and re-activated in cancer. Our goal is to identify oncofetal piRNAs, which might represent ideal cancer therapeutic targets, as they are absent in normal adult lung tissue.
Method:
We determined piRNA expression profiles from small-RNA sequencing libraries using an in-house pipeline. All sequence reads were aligned to the hg38 build of the human genome. The expression levels of fetal lung samples (n=25) and two tumour/non-malignant paired cohorts (BCCA, n=118 and TCGA, n=91; derived from non-small cell lung cancer cases) were compared. piRNAs not expressed in non-malignant samples but with comparable expression in both fetal and tumour tissues were classified as oncofetal piRNAs. In order to identify the biological functions of the identified oncofetal piRNAs, we performed piRNA/DNA binding prediction using the miRanda algorithm adjusted for piRNA-specific features.
Result:
Our results provide a comprehensive characterization of piRNA expression in both normal and tumour lung tissues, as well as an unique piRNA expression profile of fetal lung tissues. A subset of the piRNA pool expressed in lung tissues are similarly expressed between fetal lung and lung tumours, but are absent in non-malignant tissue, implying that tumour initiation might involve the reactivation of developmental pathways. More importantly, target prediction analysis revealed that the identified oncofetal piRNAs are involved in key cellular processes, such as cell proliferation, migration and survival.
Conclusion:
Our study provides an unique and comprehensive characterization of the piRNA pool of lung tissues, as well as the identification of specific similarities in piRNA expression during both organ and tumour development. These similarities between fetal and tumour tissues might represent a promising avenue for the identification of strong biomarkers or optimal therapeutic targets with little toxicity for the treatment of lung cancer. Therefore, our study provides new and promising insights for lung tumour biology and may aid in the development of novel therapeutic approaches.
