NEAT1 isoform expression in breast cancer

Numerous studies have shown that the NEAT1 (nuclear enriched abundant transcript 1) lncRNA plays a key role in cancer biology. NEAT1 is overexpressed in many solid cancers including but not limited to colorectal, ovarian, gastric, non-small cell lung and breast cancer (1-5). Conversely, NEAT1 expression is reportedly lower in haematological malignancies including chronic myeloid leukemia and acute promyelocytic leukemia (6,7). Although several studies have shown that NEAT1 is implicated in multiple cancers, the majority of studies do not delineate between NEAT1 isoforms. NEAT1 is transcribed as two major isoforms which are both initiated from the same promoter, but are vastly different in length. The long isoform, NEAT1_2 (~23 kb), is essential for the formation of paraspeckles, ribonucleoprotein bodies found in mammalian cells, which regulate gene expression through the sequestration of RNA and proteins (8). The short isoform, NEAT1_1 (~3.7 kb), is more abundant in paraspeckles (8) but has also been found in non-paraspeckle foci in the nucleus implicating NEAT1_1 in paraspeckle-independent functions (9).

A recent study by Knutsen et al., has assessed the expression of NEAT1 isoforms in breast cancer (10). Using RNA-FISH and RNA-seq expression analyses they show that NEAT1 isoforms display different expression patterns across human breast cancer subtypes. NEAT1_2 is highly expressed in human epidermal growth factor receptor 2 positive (HER2+) breast cancers whereas NEAT1_1 is more highly expressed in estrogen receptor positive (ER+) subtypes. Both isoforms are driven from the same promoter, therefore NEAT1 isoform expression is controlled post-transcriptionally. Indeed, previous studies have shown the paraspeckle protein, hnRNPK, increases the production of NEAT1_2 by negatively regulating the polyadenylation signal of the shorter NEAT1_1 isoform (8). In breast cell lines, hnRNPK is induced by growth factors, but blocked by treatment with anti-HER2 antibodies suggesting hnRNPK may play an important role in HER2 signalling (11). However, whether the increased expression of NEAT1_2 in HER2+ breast cancers is driven by hnRNPK will require additional research.

NEAT1 overexpression has been reported to be associated with poor survival in multiple cancers types (1,4,12,13). However, many of these studies are based on small samples sizes and larger cohorts are required to confirm these observations. Furthermore, a previous study showed that NEAT1_2 but not NEAT1_1 is associated with poor progression free survival in ovarian cancer patients treated with platinum-based chemotherapy (14). Notably, Kaplan Meier-plotter analysis (15), indicates that low levels of total NEAT1 (as opposed to high levels in other cancer types) is associated with relapse free breast cancer survival (logrank P=1×10¹⁶; n=1,764), however there is no association with survival when the cohort is stratified into ER+ (logrank P=0.067; n=762) and ER- breast tumors (logrank P=0.058; n=347). Therefore, it is likely that the association of total NEAT1 with improved survival, reflects that NEAT1_1 is more abundant and is expressed higher in ER+ breast cancers, which have a significantly better prognosis. The studies performed by Knutsen et al, showing that NEAT1_2 is associated with more aggressive breast cancers, highlights the importance of determining whether NEAT1_2 is associated with outcome in different breast cancer subtypes. Unfortunately, this is not possible with polyA enriched RNAseq data, such as the breast TCGA cohort, as NEAT1_2 is not polyadenylated and therefore will not be annotated in these datasets. Additional total RNAseq from cohorts with survival data will be required to conduct these studies.

Paraspeckle formation is often observed in different cell types under stress conditions. For example NEAT1 is induced under hypoxia (16), heat shock (17), mitochondrial stress (18) and viral infection (19). The upregulation of NEAT1 in malignant tissues is therefore not surprising. In summary, the study by Knutsen et al., highlights the need to perform isoform-specific studies when assessing the function of NEAT1 and the expression in normal and disease conditions. Clearly, NEAT1 plays an important role in cancer and other disease states and further research is required to identify whether specific NEAT1 isoforms will be useful cancer biomarkers or therapeutic targets.

Acknowledgments

Funding: SLE is supported by a NHMRC Senior Research Fellowship (1135932). JDF is supported by a philanthropic donation from Isabel and Roderic Allpass.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Non-coding RNA Investigation. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ncri.2020.03.02). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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