In the previous section, the established participation of paraspeckles in cancer was demonstrated using the CML context, where
BCR–ABL, the main cause of a vast majority of CMLs [
21], tends to activate c-Myc, which then represses NEAT1, which in turn prevents paraspeckle formation. This, as explained previously, allows SPFQ to resume its role as a transcription factor for apoptosis-related genes, promoting apoptosis in cancer cells [
9]. Therefore, paraspeckles can be viewed as promoting cancer due to their role in repressing apoptosis. Thus, there is a possibility that re-establishing this pathway could have therapeutic benefits. Paraspeckles have also been shown to increase resistance to apoptosis due to changes in miRNA patterns, although the exact interactions have not been identified. Increased levels of miRNA will typically lead to more double-stranded RNA (dsRNA), which can cause apoptosis. Too little miRNA will cause interferon stimulated genes (ISGs) to be expressed, which also results in apoptosis. The paraspeckle has been shown to prevent this and stabilise miRNA concentrations [
22,
23,
24]. The way this affects cancer has not been shown; however, it could possibly inhibit miRNA-induced apoptosis, allowing tumour cells to mutate in ways that alter the presence of miRNA without killing the cell. This would result in a cell that is more able to withstand random mutations, such as those undergone constantly throughout the cancer evolution process. This also means that paraspeckles effectively increase the ability of cancer cells to withstand apoptotic chemotherapies, increasing their chemoresistance potential. Additionally, paraspeckles have been shown to be induced under hypoxic conditions [
25]. Hypoxia is a well-established pathway that tumours utilise to increase their invasive, proliferative, and chemoresistant properties [
26]. Hypoxia inducible factor 2 (HIF-2) has been shown to activate
NEAT1 expression and drive the formation of paraspeckles. This means that paraspeckles could be one of the downstream mediators of the hypoxic pathway [
25]. This leads to the identification of NEAT1_2 as a possible prognostic marker due to its ability to indicate the extent of the hypoxic response within cells. There is also the possibility to serve as a therapeutic target in order to prevent cancer cells from activating the hypoxic response, which tends to result in increased chemoresistance [
26]. However, it is important to note that this study did not distinguish between either isoform of
NEAT1 leaving the possibility that the isoform NEAT1_1 is the target of HIF-2 induced gene expression of
NEAT1. This means NEAT1_1 is the downstream factor in the hypoxic pathway and, therefore, it is NEAT1_1 that could be increasing the chemoresistance of a tumour, whilst the increased paraspeckle formation is just a side product [
25]. This will be discussed further in
Section 2.2. Furthermore, paraspeckles have been shown to be an important component to the DNA damage response in oncogenic cells [
27]. NEAT1_2 suppression was shown to bring about a disruption of Ataxia telangiectasia, mutated (ATM) signalling, resulting in a weakened DNA damage response (DDR) and, thus, in enhanced replication stress [
27]. This means that NEAT1_2 expression and the resulting paraspeckle formation in tumour cells results in a greater resistance to chemotherapies that cause replication stress. Furthermore, it is important to note that in this study NEAT1_2 was specifically suppressed instead of simply preventing
NEAT1 expression in general. This is important because by downregulating the isoform that actually forms the paraspeckle it eliminates the possibility of NEAT1_1 producing effects not related to the paraspeckle. Despite this however,
NEAT1 and by extension, the paraspeckle has also been shown to suppress tumour formation. This is due to its interaction with p53, a protein heavily involved in tumour prevention. This protein is involved in multiple pathways related to the prevention of cancer such as those resulting in apoptosis and senescence [
28]. Moreover, p53 also tends to suppress tumour progression without halting the cell cycle or killing the cells in ways that have not yet been fully described [
29]. Recently,
NEAT1 has been shown to be a highly significant downstream regulator of this p53 tumour suppressor pathway [
30,
31,
32], which results in tumour suppression and decreased chemoresistance. In fact, a p53 binding motif was found in the promotor of
NEAT1 and activation of p53 resulted in the expression of
NEAT1 [
30]. This study also demonstrated that attenuation of
NEAT1 resulted in a decreased ability for p53 to supress tumours, proving that
NEAT1 is partly responsible for the tumour suppressor effects of p53 [
30]. Furthermore, in pancreatic cancer, the loss of
NEAT1 increases the rate of acinar-to ductile metaplasia (ADM), a process of dedifferentiation, which is an early stage of pancreatic cancer formation [
30]. This is due to
NEAT1 aiding in the expression of several pancreatic differentiation factors, such as Basic Helix-Loop-Helix Family Member A15 (Bhlha15) and SRY-Box Transcription Factor 9 (SOX9) [
30], as well as tumour suppressor genes that tend to inhibit cancer progression, such as Plexin A4 (Plxna4), which is involved in the prevention of vascular endothelial growth factor (VEGF), a key protein in angiogenesis and growth [
33]. Therefore, the induction of Plxna4 expression by
NEAT1 results in decreased proliferative abilities and decreased angiogenic properties of tumours, through the inhibition of VEGF [
34]. The role of
NEAT1 in expressing differentiation factors is especially important when considering cancer stem cells (CSCs). This subpopulation present in tumours can proliferate quicker, are more invasive and are more resistant to drugs [
35]. The latter is due to numerous factors including the presence of the ATP binding cassette (ABC) family of membrane proteins designed to protect stem cells. Such proteins are crucial to prevent the accumulation of foreign substances in stem cells, which need to conserve the integrity of their DNA sequences in order to pass on to daughter cells DNA that have not been mutated. However, such proteins in CSCs promote chemoresistance by preventing drugs from entering the cell [
36]. This could potentially link paraspeckles with the prevention of CSC formation, which could possibly be a very useful therapeutic target to prevent CSC development, and thus significantly decreases chemoresistance. This role of the
NEAT1 transcripts in promoting differentiation is interesting since in smooth muscle, paraspeckles have the opposite effect, tending instead to promote dedifferentiation through sequestering WD Repeat Domain 5 (WDR5) within the paraspeckle, resulting in a decrease in the expression of smooth muscle genes [
37]. This further highlights the important notion that many interactions are cell-specific and that the paraspeckle may have a different or even an opposite effect in different cellular contexts. Considering the previously mentioned chemoresistance inhibiting properties, it is no surprise that NEAT1_2, which is the long 3′ processing variant that forms the paraspeckle, is generally considered a tumour suppressor, where lower levels indicate a poorer prognosis such as in colorectal cancer and can, thus, serve as a potential prognostic marker for the disease since higher. In fact, NEAT1_2 levels have been linked with better prognosis, due to it lowering the chemoresistance of tumours [
38].