It is estimated that less than 2% of the human genome is made up of genes that encode proteins, while the remaining 98% of the genes are transcribed to RNA without going through the process of encoding proteins. Moreover, non-coding RNAs (ncRNAs) were considered of no particular use in the genome. However, it is now apparent that they play various functional roles within cells. They are categorized based on their size and do not contain long open reading frames. Small ncRNAs such as microRNAs (miRNAs), small interfering RNAs (siRNAs), and PIWI-interacting RNAs (piRNAs) are non-coding transcripts with a length of less than 200 nucleotides. On the other hand, long non-coding RNAs (lncRNAs) are RNA molecules whose length exceeds 200 nucleotides. As of right now, up to 100,000 lncRNAs are known. Different tissues and cancer types express lncRNAs in different ways (Mirzaei et al. 2022a). The lack of an open reading frame (ORF) is the reason lncRNAs cannot encode proteins. Human cancer develops as a result of mutations in noncoding RNAs. RNA polymerase II appears capable of transcribing, capping, polyadenylating, and splicing lncRNAs. Furthermore, the promoter regions, exons, antisense sequences, enhancer sequences, untranslated regions (UTRs) like 3/ and 5/, introns, and intergenic and intragenic regions of the genome can all be used to execute the biogenesis of lncRNAs. Moreover, lncRNAs can regulate target expression through many mechanisms (Fig. 1). LncRNAs can influence biological processes and maintain homeostasis by acting as a signal, decoy, guide, scaffold, and miRNA modulator (Elimam et al. 2024a, c; El-Boghdady et al. 2023).
The position of lncRNAs in the cytoplasm or nucleus of cells determines how they function. Increasing evidence of research indicates that lncRNAs that reside in the nucleus are involved in epigenetic and transcriptional regulation of genes, including DNA methylation, histone modification, chromatin remodeling, interactions with proteins, and transcription factors within the nucleus. Conversely, the lncRNAs that affect the expression of genes at both transcriptional and post-transcriptional levels can be found in the cytoplasm. These cytoplasmic lncRNAs can interact with miRNAs by functioning as competitive endogenous RNAs (ceRNAs), which can impact cytoplasmic proteins and modify RNA metabolism (Fig. 1) (Mirzaei et al. 2022a, Doghish et al. 2024).
Fig. 1LncRNAs have a crucial role in the alteration of gene expression. LncRNAs exert influence on mRNA stability in various routes such as direct binding to target mRNAs, interactions with RNA-binding proteins, competition with miRNAs as competing endogenous RNAs, regulation of mRNA decay pathways, and interference with transcription
Owing to the crucial functions of lncRNAs in cells, they can control the development of tumors, the invasion, and the resistance to medication. According to recent research, lncRNAs are the main regulators of signaling networks in cancer. lncRNAs typically impact miRNAs in malignancies, whereby modulating miRNA expression, lncRNAs impact tumor cell migration and survival (Mirzaei et al. 2022a). Additionally, lncRNAs that promote tumors, like CCAT2, can stop cancer cells from apoptosis (Gao et al. 2020a). Significantly, to support anti-tumor immunity against tumor cells, lncRNAs can encourage the infiltration of immune cells such as B cells, T cells (including CD8 + and CD4 + T cells), neutrophils, and dendritic cells (Zhang et al. 2020).
Role of lncRNAs in EMT, invasion, and metastasis of PCaThe EMT mechanistic involves the conversion of normal epithelial cells to mesenchymal cells which proliferate easily (Nakazawa et al. 2017). During this process, the epithelial cell markers are suppressed, along with the enhancement of mesenchymal markers, leading to the encouragement of invasion and proliferation (Odero-Marah et al. 2018; Elimam et al. 2024b). Various lncRNAs could modulate EMT by targeting EMT-linked transcriptional factors (Heery et al. 2017). LncRNAs could also act as PRC2 modulators which exhibit a significant role in silencing some genes (Margueron and Reinberg 2011, Simon and Kingston 2009). Recent studies have also indicated that several signaling pathways including AR signaling, STAT3 signaling, and others are involved in inducing and maintaining EMT (Shen et al. 2022). Hence, we attempt to summarize the current knowledge about EMT-related lncRNAs as well as those associated with development, progression, and metastatic capability in PCa.
One of the lncRNAs that modulate the EMT progression is MALAT-1. This lncRNA targets the miR-145, thus promoting PCa development. It has also been shown that MALAT1 modulates the downstream axis SMAD3/TGFBR2 (Zhang et al. 2021) (Table 1). In CRPC, MALAT1 was overexpressed, interacting with EZH2. It also enhanced the invasive and migratory capabilities of PCa cells via repressing target genes such as DAB2IP and BRACHYURY (Wang et al. 2015). Lu et al. disclosed that MALAT1 underscores the beneficial action of the natural product quercetin flavonoid. Quercetin inhibited cancer cell development and tumor growth, suppressed the EMT process, and promoted apoptosis through the downregulation of MALAT1 expression (Lu 2020) (Table 1). A study assessing MALAT1 expression in urinary samples revealed that it was markedly elevated in PCa, suggesting that urinary MALAT1 could serve as a diagnostic marker for PCa (Wang et al. 2014a). CCAT2 is another lncRNA that was markedly elevated in PCa and contributes to the development of PCa. Conversely, silencing CCAT2 reduces PCa progression. Additionally, CCAT2 is implicated in promoting EMT via targeting N-cadherin, vimentin, and E-cadherin (Zheng et al. 2016) (Table 1).
In the same context, DANCR is another PCa modulator and is correlated with advanced stages (Jia et al. 2016). High levels of lncRNA-ATB were reported as PCa promoters via stimulating EMT. Conversely, its suppression alleviates to a great extent the proliferation, invasion, and EMT.
Additionally, overexpression of lncRNA-ATB promoted, and knockdown of lncRNA-ATB inhibited the growth of prostate cancer cells via regulations of cell cycle regulatory protein expression levels. In addition, lncRNA-ATB stimulated EMT associated with ZEB1 and ZNF217 expression levels via ERK and PI3K/AKT signaling pathways (Xu et al. 2016). ZEB1 functions primarily as a transcriptional repressor of epithelial markers such as E-cadherin, while simultaneously promoting the expression of mesenchymal markers like vimentin and N-cadherin. This dual action is essential for the induction of EMT, which is often associated with aggressive tumor behavior and treatment resistance in various cancers. ZEB1 influences epigenetic modifications, such as DNA methylation and histone modifications, which further stabilize the EMT phenotype. For instance, ZEB1 can recruit chromatin-modifying enzymes like histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) to maintain the repression of epithelial genes (Lindner et al. 2020, Wu et al. 2020a) (Table 1).
Another carcinogenic entity is PlncRNA-1, first recognized in PCa, where it regulates the cell cycle and Cyclin D1. As well, PlncRNA-1 encourages EMT by influencing the TGF-β1 axis (Jin et al. 2017, Mirzaei et al. 2022b). Moreover, PlncRNA-1 is nominated as a molecular inhibitor, safeguarding the AR from being inhibited by miRNA-34c and miRNA-297 in PCa (Fang et al. 2016) (Table 1).
UCA1 is also highly expressed in PCa tissue and linked with bad outcomes (Wang et al. 2017a). Its expression was directly associated with Gleason scores, tumor aggressiveness, and bad prognosis. One study revealed a correlation between KLF4 expression in PCa tissue and UCA1 levels, highlighting that the suppression of UCA1 resulted in low levels of KLF4 (Na et al. 2015). KLF4 exerts a critical function in cellular proliferation in metastasis Additionally, UCA1 is reported to function as a ceRNA, downregulating miRNA-204 (Su et al. 2017a). MiR-204 inversely regulates the Sirt1 gene, with overexpression of UCA1 leading to increased Sirt1 levels. Indeed high levels of Sirt1 are linked with cancer cell invasion, migration, and EMT (Wang et al. 2016) (Table 1). Another study disclosed that UCA1 promotes PCa via suppressing miRNA-143 (Yu et al. 2020).
In parallel, ZEB1-AS1 promotes PCa development by targeting ZEB1. Worthy noted that ZEB1 facilitates various tumor biological processes, such as EMT. The upregulation of ZEB1-AS1 modulates the transcription of BMI1 via inhibiting miRNA-200c (Su et al. 2017b). SChLAP1 is shown to characterize an aggressive case of PCa. It opposes the SWI/SNF chromatin-modifying complex, which possesses tumor-preventing role. The SChLAP1 orchestrates tumor cell invasiveness as well as is substantially linked to unfavorable clinicopathological features and bad prognosis (Prensner et al. 2013, Kidd et al. 2021) (Table 1).
HOTAIR is also upregulated in PCa and promotes its proliferation, while its inhibition hinders tumor progression (van der Laak et al. 2021). HOTAIR exerts an oncogenic effect via influencing EZH2, hepaCAM, and MAPK cascade (Battistelli et al. 2017). HOTAIR acts as a scaffold to recruit PRC2 to specific genomic loci. The complex includes EZH2, which is responsible for catalyzing the trimethylation of H3K27 (H3K27me3). Moreover, HOTAIR mediates a switch from histone acetylation to methylation. Specifically, it promotes the conversion of H3K27 acetylation (a marker of active transcription) to H3K27 methylation (a marker of repression). This switch inhibits the transcription of genes like E-cadherin, thus facilitating processes such as EMT in cancer cells (Song et al. 2019, Wasson et al. 2020). Besides, HOTAIR performs its effects via modulating miRNA-34a and miRNA-568 (Wu et al. 2015, Liu et al. 2015a). The lncRNA PCA3 is implicated in the EMT of PCa, where it promotes EMT-promoting genes and abolishes genes that antagonize EMT. Furthermore, PCA3 suppression has been shown to inhibit AR signaling, as well as cell growth and viability (Lemos et al. 2016).
Preceding reports indicated that PCA3 performs its oncogenic role via suppressing miR-1261 which targets the protein kinase D3 gene (Iwasaki et al. 2016). Over and beyond, the lncRNA PCMF1 is involved in the metastasis process in PCa. Cui and his colleagues disclosed that stimulates EMT via modulating miRNA-137. On the flip side, suppressing PCMF1 reversed this effect, restoring miRNA-137’s ability to inhibit the Twist1 protein (Cui et al. 2023) (Table 1). In tandem, the LINC01296 encourages EMT and metastasis in PCa via modulating the PI3K-AKT cascade. Elevation of LINC01296 was markedly associated with unfavorable clinicopathological features and bad prognosis (Wu et al. 2017). Another study reported that LINC01006 advocated PCa development by inhibiting the miRNA-34a-5p (Ma et al. 2020).
Table 1 LncRNAs implicated in PCa through the regulation of EMT, invasion, and metastasisRole of lncRNAs in PCa progression (apoptosis, proliferation, and tumor growth)Numerous researches have demonstrated that lncRNAs perform critical regulatory roles in tumor growth. For instance, GAS5 is downregulated in CRPC, increasing apoptosis and decreasing cell survival in vitro via modulating PI3K-AKT cascade and the miRNA103 (Pickard et al. 2013). The lncRNA SOCS2-AS1 is markedly upregulated in PCa and abrogates cell death (Misawa et al. 2016). Diverse organs are enriched with the lncRNA POTEF-AS1,however, it stimulates PCa development. POTEF-AS1 enhances tumor cell development and hinders apoptosis via TLR and apoptosis cascades (Misawa et al. 2017b) (Fig. 2) (Table 2).
NEAT1 is markedly elevated in PCa samples, suggesting its oncogenic properties (Nitusca et al. 2021). NEAT1 is implicated in diverse oncogenic mechanisms such as invasion, and migration (Fu et al. 2016) (Table 2). MEG3 (Maternally Expressed 3) expression levels were downregulated in PCa (Luo et al. 2015). In vitro studies demonstrated that MEG3 inhibited cell growth and triggered cell death. It was shown to enhance the expression of the pro-apoptotic protein Bax and activate caspase3 while repressing Bcl-2 and Cyclin D1, both of which are linked to cell survival and proliferation. Additionally, MEG3 performs its antitumor effects via activation of p53, which leads to decreased cell proliferation and promotes apoptotic processes (Zhou et al. 2007) (Table 2).
PVT1 is markedly elevated in PCa and plays a potential role in regulating tumor growth and apoptosis via modulating miR-146a (Liu et al. 2016). Moreover, another study showed that the suppression of PVT1 hindered PCa progression by suppressing KIF23 through the stimulation of miRNA-15a-5p (Wu et al. 2020b) (Fig. 2). The oncogenic SPRY4-IT1 is markedly raised in PCa and activates cancer cells’ growth and development. On the other side, suppression of SPRY4-IT1 using siRNA resulted in reduced cellular proliferation and invasion in PC3 cells, along with an increase in apoptosis (Lee et al. 2014, Misawa et al. 2017a) (Table 2). PCAT1 was first identified in PCa but has since shown potential as a biomarker for various cancer types (Prensner et al. 2014a, Liu et al. 2015b, Shi et al. 2015). A transcriptome sequencing study focused on PCa identified 121 unannotated non-coding RNAs in PCa (Prensner et al. 2011). Other investigations have demonstrated that PCAT-1’s role in promoting PCa cell proliferation relies on the modulation of the c-Myc protein (Prensner et al. 2014b) (Table 2).
LincRNA-p21 was recorded as a PCa suppressor where it attenuates growth and colonization of PCa. Furthermore, it triggered cell death and modulated p53. Remarkably, suppressed LincRNA-p21 is linked with aggressive clinical features and bad prognosis (Wang et al. 2017b).
Intriguingly, AR-regulated lncRNAs, CRPC LncRNAs, are elevated in CRPC. Suppression of lncRNAs PRKAG2AS1 and HOXCAS1) lessened CRPC tumor growth, showing repression of AR. Precisely, subcellular localization of the splicing factor, U2AF2, with an essential role in AR splicing machinery was modified according to the level of HOXCAS1 (Takayama et al. 2020) (Fig. 2).
As mentioned in the current review, there is great progress and knowledge about the interplay of lncRNAs in proliferation, invasion, apoptosis, EMT, and metastasis in PCa; however, still diverse gaps remain. The manner through which lncRNAs interact with multiple protein targets and transcription factors to regulate genes involved in proliferation, invasion, and migration is not fully elucidated. The accurate underlying mechanisms through which these lncRNAs perform their role in EMT and metastasis as well as affect the integrity of the epithelial cell junctions are not fully investigated. Moreover, some lncRNAs mediate their roles via interactions with chromatin modifiers, transcription factors, and modulating miRNAs, but detailed mechanistic insights are still lacking and need further mechanistic studies. Another key point that should be taken into consideration is the heterogeneity of the PCa; thus, the regulation of the lncRNAs is variable according to the tumor subtypes, malignant stages, and their molecular features.
Fig. 2Role of lncRNAs in the progression of PCa including apoptosis, proliferation, and tumor growth. LncRNAs affect key cellular pathways, by interacting with genes and signaling networks, promoting tumorigenesis and disease progression. KIF23: Kinesin-like protein; IKKα: I Kappa B Kinase Alpha; TLR: Toll-like receptors
TRPM2-AS is elevated in PCa and associated with bad outcomes. In vitro research revealed that its silencing leads to the enhancement of apoptosis. Importantly, TRPM2-AS was disclosed as a potential coordinator of diverse genes related to survival, and the cell cycle (Orfanelli et al. 2015), (Lavorgna et al. 2015) (Table 2).
Table 2 LncRNAs implicated in PCa progressionRole of chemotherapy in the treatment of PCaDocetaxel-based chemotherapy initially demonstrated a slight increase in survival when compared to mitoxantrone-based therapy as first-line chemotherapy in 2004; therefore, chemotherapy has been essential in the treatment of metastatic CRPC (mCRPC) (Antonarakis and Armstrong 2011). The antimitotic drug docetaxel has been shown in recent years to suppress androgen receptor (AR) transcriptional activity and its longstanding ability to prevent microtubule disassembly. Docetaxel can prevent the AR from moving to the nucleus in response to ligand-dependent signaling pathways as well as androgens. By influencing the gene promoter, docetaxel also suppresses the expression of the AR gene. It raises the amounts of Forkhead box O1 (FOXO1), a strong transcriptional repressor of AR (Fitzpatrick and de Wit 2014). Abiraterone acetate and enzalutamide are two new oral antiandrogen medications that have increased survival in pre- and post-docetaxel situations since the approval of docetaxel (Ryan et al. 2013, Beer et al. 2014). Furthermore, post-docetaxel patients’ lives have been prolonged with cabazitaxel, a second and stronger taxane (De Bono et al. 2010).
Both docetaxel and paclitaxel are recommended as well-known drugs for the chemotherapy of prostate tumors. They also serve a similar purpose in cancer treatment, which is focused on preventing microtubule depolymerization, disrupting microtubule equilibrium, and so delaying the advancement of the cell cycle (Hashemi et al. 2023). Recent evidence suggests that Doxorobucin has pleiotropic anticancer properties, including its participation in immunomodulation, apoptosis, senescence, autophagy, ferroptosis, pyroptosis induction, DNA damage, and the generation of reactive oxygen species (ROS) (Kciuk et al. 2023). It was concluded that Doxorubicin increases the cytotoxicity and apoptosis caused by TRAIL targeting prostate cancer cells (Wu et al. 2002; El-Hawwary et al. 2022; Bakr et al.2021).
Therapy resistance to the major treatments in PCaThe PCa poses a significant health challenge due to its resistance to radiation therapy and chemotherapy. Patients with metastatic PCa frequently have a dismal prognosis, even with rigorous therapies utilizing a variety of techniques, while those with localized PCa typically have a better survival rate (Sarfraz et al. 2024). In addressing PCa, chemoresistance (CR) and radioresistance (RR) present major problems. CR represents a major hurdle in PCa management. Even though CT is a common therapeutic strategy for PCa, the development of CT resistance is a considerable clinical barrier. A comprehensive understanding of the underlying mechanics is crucial for the efficient treatment of PCa (Bhagirath and Saini 2019).
There is growing evidence that lncRNAs have a significant role in carcinogenesis, specifically in PCa. Furthermore, lncRNAs play a significant role in treatment resistance in PCa (Sarfraz et al. 2024), progression and CR being significantly overexpressed in CRPC cells. Silencing of HOXD-AS1 reduced cell proliferation in vitro and inhibited tumor progression in vivo in PCa by triggering the cell cycle arrest transition from G2 to M phase (Gu et al. 2017) (Table 3). Wang et al. (2021) demonstrated that in docetaxel-resistant PCa cells and tissues, the lncRNA OGFRP1 was highly expressed, additionally,it was possible to enhance these cells’ susceptibility to docetaxel and paclitaxel both in vitro and in vivo by suppressing OGFRP1 via the upregulation of miR149-5p and the subsequent downregulation of IL-6. Functionally, OGFRP1 was capable of binding to miR-149-5p and encouraging the overexpression of IL-6, an essential modulator of cancerous activity both in vivo and in vitro (Wang et al. 2021) (Table 3).
CCAT1 is another oncogenic lncRNA implicated in paclitaxel resistance in PCa; a study by Li et al. (2020) demonstrated that knocking out CCAT1 prevents the development, migration, and expansion in PCa cells. Sponging of miR-24–3p by CCAT1 hinders it from the activation of its downstream protein (FSCN1) as a consequence of this association; FSCN1 is highly expressed which increases paclitaxel tolerance (Li et al. 2020) (Table 3).
Moving to another oncogenic lncRNA; HOTTIP which is highly expressed in PCa and associated with CR. Jiang et al. (2019) demonstrated that HOTTIP suppression inhibited the Wnt/β-catenin pathway leading to reduced CDK4, cyclin D1, and β-catenin expressions; consequently, the development of PCa cell and cell cycle will be inhibited; moreover, the sensitivity of the cells to cisplatin will be enhanced (Jiang et al. 2019) (Table
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