Abstract

Introduction

lncRNAs are widely distributed in prokaryotic and eukaryotic genomes. Despite being one of the most conserved and rapidly evolving sequences in vertebrate genomes, non-protein-coding RNAs (ncRNAs) have long been considered to lack functionality. In the human genome, there are 5,446 lncRNA genes identified out of a total of approximately 24,000 full-length cDNAs [1]. When compared to protein-coding transcripts, lncRNAs are smaller in size, ranging from 200 nt to thousands of nt, with an average exon count of 2.9 [2]. They also possess longer introns and exhibit higher non-poly(A) ratios than protein-coding transcripts [3]. According to their position relative to protein-coding genes, lncRNAs can be categorized as antisense RNAs, lncRNAs, sense overlapping transcripts, sense intronic transcripts, and processed transcripts [3].

LncRNAs represent one of the regulatory components of the eukaryotic genome and play diverse functions that are essential for a variety of biological processes and for coordinating gene expression. Compared to microRNAs (miRNA), lncRNAs can fold into intricate secondary and higher structures, thereby providing a greater potential for target recognition [4]. lncRNAs play diverse roles in gene expression. The functional roles of lncRNAs can be summarized into four mechanisms: signaling, decoy, guidance, and scaffolding [5].

Signaling involves the spatiotemporal expression of gene regulation pathways. lncRNAs regulate transcription factors (TFs), including modulating TF activity, interacting with TFs to influence gene expression, and facilitating the nuclear translocation of TFs.

Decoy functions by guiding target factors to specific regions. As competitive endogenous RNAs (ceRNAs), lncRNAs act as decoys that can effectively consume miRNAs while competitively binding to target genes to regulate their expression.

Guidance recruits the target proteins to either cis- or trans-regulate the target genes. Upon signals of DNA damage, the proximal promoters of cyclin genes are transcribed into lncRNAs, which subsequently recruit RNA-binding proteins to modulate transcriptional processes [6]. lncRNAs bind to polynuclear restriction complex 2 (PRC2) and induce Histone H3 lysine-27 trimethylation, leading to the inhibition of gene transcription and trans-regulation of coding genes [7]. lncRNAs interact with chromatin-modifying proteins and recruit them to specific regions to inhibit the expression of adjacent loci, thus cis-regulating the neighboring genomic elements [8].

Scaffolding facilitates the aggregation of multiple proteins into functional complexes. lncRNAs serve as scaffold molecules that regulate protein delivery. The translation process is regulated through interactions between protein-coding genes and their homologous antisense transcripts, antisense ncRNA pairs with the mRNA bases to form RNA double strands that cover key cis-elements within mRNA, subsequently guiding the binding of mRNA isoforms with splicing regulatory proteins for alternative splicing [9]. The lncRNA Xist participates in chromosome dosage compensation by regulating X chromosome inactivation [10], forms RNA double-strands with the antisense transcript Tsix through annealing, and subsequently generate small interfering RNAs upon Dicer processing, thereby participating in repressive chromatin modifications [11].

Furthermore, lncRNA can actively contribute to the regulation of pluripotency in embryonic stem cells (ESC) through the targeted modulation of gene expression. Additionally, lncRNAs have been shown to play significant roles in various human diseases, including cancer, endocrine disorders, neurodegenerative and psychiatric conditions, cardiovascular diseases, hypertension, stroke, immune dysfunction, and autoimmune disorders [4].

This review provides a comprehensive summary of how lncRNAs can alter cell differentiation potential and inhibit or promote the formation of functionally mature channels by regulating the spatiotemporal expression of coding genes through the binding of specific TFs, priming targets, recruiting protein-regulated target genes, and recruiting protein-functional complexes. During tissue repair and regeneration, lncRNAs regulate the self-renewal capacity of cells and participate in cell differentiation. Moreover, during injury or disease, lncRNAs contribute to cellular activation and differentiation for effective tissue and organ repair and regeneration. In developmental contexts, cell stemness refers to the undifferentiated state observed in ESCs and induced pluripotent stem cells (iPSCs). lncRNAs can dynamically modulate cell stemness through gene expression regulation mechanisms such as epigenetic modifications and intricate signaling pathways that orchestrate tissue development events. Cancer initiation and progression are significantly influenced by alterations in cell stemness. Here we have discussed the involvement of lncRNA-regulated cancer cell stemness in the proliferation, migration, invasion, and metastasis of various tumo cells. Several examples are illustrated in Table 1.

lncRNA regulates cell differentiation

In biology, the regulation of cell differentiation is a pivotal research direction. Recent studies have revealed that certain epigenetic regulatory factors, such as histone modification and DNA methylation, can influence gene expression, thereby modulating the trajectory of cellular differentiation. Additionally, signal transduction pathways have been shown to play a crucial role in governing cell differentiation, and aberrant activation or inhibition of molecules within these pathways can result in abnormal cellular differentiation patterns. Remarkable progress has been made in the field of biotechnology in investigating the regulation of cell differentiation. For instance, researchers can precisely manipulate gene expression within cells using gene-editing technologies, thus elucidating the key factors that are involved in cellular differentiation. Certain previous studies have demonstrated that AAV-ie-K558R [12] and AAV-Net1 [13] promote trans-differentiation from supporting cells to hair cells within the mouse cochlea and knocking out Foxg1 in supporting cells facilitates their trans-differentiation into hair cells [14]. Recent research has highlighted the crucial role of lncRNAs in cellular differentiation. By employing various mechanisms, lncRNAs effectively coordinate and regulate cell differentiation.

lncRNAs are involved in the spatiotemporal expression of genes through signal transduction, thereby regulating differentiation. Four neuronal lncRNAs have been identified: RMST, lncRNA_N1, lncRNA_N2, and lncRNA_N3 [27]. RMST and lncRNA_N1 were specifically expressed in the brain. lncRNA_N3 interacts with SUZ12 to participate in epigenetic gene silencing. lncRNA_N2 maintains the cytoplasmic levels of miR-125B and LET7, promoting the neurogenesis of neural progenitor cells [27]. The transcript of metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is a highly conserved 8.7 kb RNA molecule. Malat1 acts as a downstream target of myogenic proteins and potently regulates skeletal muscle growth and development [28]. Myostatin downregulates Malat1 expression in skeletal muscle and inhibits Malat1 transcripts levels in proliferating primary human myoblasts, whereas it has been shown that myostatin does not impact the expression of Malat1 in proliferating mouse C2C12 myoblasts [28]. The ANCR gene, located on human chromosome 4, produces a single 855-bp RNA transcript known as LncRNA NR_024031 or anti-differentiation ncRNA (ANCR) [29]. Within the epidermal tissue progenitor-containing compartment, ANCR prevents the expression of differentiation-related genes to maintain an undifferentiated state. Deletion of ANCR disrupts the normal expression pattern of TFs (such as CEBPA [30], GRHL3 [31], and HOPX [32]) involved in epidermal differentiation. The lncRNA RNCR2 exhibits high expression levels in differentiating mouse retinal cells and is predominantly localized within the nucleus [33]. Knockout of the RNCR2 gene and ectopic nuclear export of RNCR2 RNA results in an augmented population of amniotic cells and Müller glial cells while concomitantly reducing the number of photoreceptor cells [33].

lncRNAs participate in cell differentiation by directing target factors to specific regions to function as decoys. Muscle-specific long noncoding RNA (lnc-MD1) expression is localized in the cytoplasm and is induced during muscle cell differentiation [34]. Functioning as a ceRNA, lnc-MD1 competes with miR-133 and miR-135 for binding, thereby regulating the distribution of these miRNAs to their targets and facilitating post-transcriptional gene regulation [35,36]. lnc-MD1 functions as a competitive endogenous RNA (ceRNA) by binding to miR-133 and miR-135, thereby competing for their mRNA targets such as MAML1 and MEF2C, and plays a crucial role in regulating the timing of myocyte differentiation [34]. lncRNA H19, a well-known maternally expressed and paternally imprinted gene [37], does not encode proteins, but rather encodes a 2.3 kb long H19 ncRNA. H19 was found to promote the differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts by targeting miR-141 and miR-22, thereby activating the Wnt/β-catenin pathway and facilitating hMSCs osteoblastic differentiation [38]. H19 acts as a ceRNA for two miRNAs, miR-141 and miR-22. H19 and its exon 1 encode two evolutionarily conserved miRNAs [39]: miR-675-3p and miR-675-5-p, which are involved in myoblast differentiation, skeletal muscle satellite cell differentiation, and skeletal muscle regeneration. MiR-675-3p and miR-675-5-p exert their pro-myogenic effects by targeting Smad1 and Smad5 (TFs mediating the anti-differentiation effect of the BMP pathway), and the DNA replication initiation factor Cdc6 [40]. Sirtuin 1 (Sirt1) is an NAD-dependent deacetylase involved in myogenesis [41]. During C2C12 cell myogenic differentiation, Sirt1 and Sirt1-AS exhibit decreased expression. It has been shown that, miR-34a targeting Sirt1 gradually causes its accumulation [41]. MiR-34a reduces the abundance of Sirt1 mRNA by binding to its target site within the 3’UTR region. Overexpression of the lncRNA Sirt1-AS leads to increased levels of the corresponding protein, thereby counteracting the miR-34a-mediated downregulation of SIRTUIN 1 [41]. PU.1, an Ets family TF, has been shown to plays a crucial role in lymphocyte differentiation in the bone marrow [42]. lncRNA PU.1-as acts as an antisense transcript for PU.1. lncRNA PU.1-as forms a double-chain complex with PU.1 mRNA, mRNA/AS lncRNA, which hinders the translation of PU.1 mRNA [42].

lncRNAs recruit target proteins to cis- or trans-regulate target genes, thereby affecting cell differentiation. The lncRNA ANCR is involved in the regulation of osteoblast differentiation of mesenchymal stem cells through its interaction with the Runx2 gene [43]. Specifically, ANCR physically interacts with EZH2 at its 3’ end within the 305-nt region. EZH2 inhibits gene expression by catalyzing histone H3 lysine 27 methylation in the promoter regions of the target genes [44]. EZH2 specifically mediates histone H3 lysine 27 methylation within the promoter region of Runx2, consequently impeding its regulatory function exerted by Runx2 on osteoblast differentiation [43]. The lncRNA H19 and its encoded miR-675 promote osteoblastic differentiation of human bone marrow mesenchymal stem cells, and miR-675 is involved in regulating H19’s osteogenic effect [45]. The H19/miR-675 axis negatively regulates TGF-b1 expression in hMSCs, leading to the down-regulation of TGF-b-phosphorylated Smad3 and subsequently attenuating the recruitment of Smad3 to HDAC4/5 [46]. This reduces the binding affinity between HDAC4/5 and the runt-related TF 2 (Runx2) DNA sequence [47]. HDAC4/5 activity-dependent TGF-b1 inhibits the osteogenic differentiation of hMSCs; however, decreased expression of histone deacetylase HDAC4/5 due to TGF-b1 downregulation impedes hMSCs’ commitment towards an osteoblastic lineage. Upregulation of H19 expression stimulated endogenous TGF-b1 expression, thereby inducing tendon differentiation and repair [48]. H19 promotes tendon differentiation by targeting miR-29b-3p, which downregulates the expression of key tendon marker genes, including SCX, MKX, EGR1, TNMD, FMOD, and DCN. Specifically, miR-29b-3p binds to TGF-b1 within its coding region and targets COL1A1 in skin fibroblasts post-transcriptionally. lncRNA SRA transcripts are present in distinct ribonucleoprotein complexes and they exhibit selective interactions with steroid receptors, thereby activating their transcriptional activity [49]. The noncoding RNA steroid receptor activator (SRA) functions as a coactivator of MyoD during skeletal muscle differentiation [50]. SRA acts as a coactivator specifically for MyoD-E12, promoting the conversion of MyoD-induced mouse fibroblasts into squamous myocytes [50]. The yin-yang 1 (YY1)-associated muscle lncRNA (Yam-1) is a muscle-specific lncRNA expressed in the nucleus and cytoplasm with a transcript length of 923 nt. Yam-1 has been shown to function as an anti-myogenic factor during in vivo muscle regeneration. It interacts with the TF YY1 in the promoter region and cis-regulates miR-715 to inhibit Wnt7b levels [51]. In additionally, Yam-2 promotes early stage myogenic differentiation. The bone morphogenetic proteins (BMP)/OP-responsive gene (BORG) represents a commonly targeted gene by BMPs. In the C2C12 mouse myoblast cell line, transfection with antisense oligonucleotides targeting BORG partially inhibited BMP-induced alkaline phosphatase activity, thereby impeding the differentiation of C2C12 cells into osteoblasts [52]. Nkx2.2 is a pivotal TF involved in the differentiation of neural stem cells into oligodendrocytes [53]. lncRNA Nkx2.2AS acts as an endogenous antisense transcript of Nkx2.2 gene, comprising a 4.3 kb cDNA that exhibits specific cytoplasmic expression patterns [54]. While positively regulating the mRNA level of Nkx2.2AS, overexpression of this lncRNA also leads to the upregulation of the corresponding Nkx2.2 mRNA levels within neural stem cells and subsequently induces their differentiation into oligodendrocyte lineages [54]. The lncRNA Evf-2 is transcribed from a highly conserved sequence located between the two Dlx-5/6 genes during neuronal differentiation in the brain [55]. Evf-2 interacts with the homeodomain protein Dlx-2 and selectively enhances the activity of the Dlx-5/6 enhancer region through a targeted mechanism specific for homeodomain binding [55].

lncRNAs can act as scaffolds for aggregating multiple proteins to form functional complexes that regulate differentiation. The nuclear localization of Men epsilon (ε) and Men beta (β) was significantly upregulated at paraspeckles during myoblast differentiation, which resulted in a 3.2-4.9 fold increase in expression levels [56]. lncRNA Men ε, also known as Neat1, is derived from mouse chromosome 19qA and spans approximately 3.2 kb in length. lncRNA MEN β represents an unspliced transcript spanning around 23 kb, with its 3’ end being subjected to RNase H digestion resulting in a short poly(A)-enriched segment formation [57]. The tRNA-like structure generated by MEN β/MEN β locus transcript through RNase P action can also undergo subsequent cleavage mediated by RNase Z enzyme activity. lncRNA MEN ε/β exhibits with Non-POU-domain-containing, octamer binding protein (also known as p54/nrb) complex crucial for initial establishment and maintenance of stable paraspeckles architecture [56]. The transcript size of the nuclear factor of activated T cells (NFAT) non-coding inhibitor (NRON) gene ranges from 0.8-3.7 kb [58]. NFAT, a calcium-sensitive TF, plays a crucial role in T cell receptor-mediated immune responses by regulating immune cell differentiation. The direct interaction between the lncRNA NRON and importin-beta 1 modulates NFAT activity. Furthermore, lncRNA NRON specifically regulates the nuclear trafficking of NFAT, thereby controlling its transcriptional activity [58].

lncRNA regulate cell regeneration and tissue development

Recently, significant advances have been made in biological science regarding the regulation of cell regeneration. Through the investigations of cell surface receptors, signaling pathway molecules, and TFs, researchers have been able to elucidate the intricate interactions and regulatory networks of multiple signaling pathways involved in cellular differentiation processes. Researchers have been able to identify key cells with regenerative potential during embryonic development, offering novel insights into tissue and organ regeneration. For instance, Lgr5-positive progenitors in mammals can regenerate into hair cells [59] and researchers have enhanced this regeneration process by overexpressing Rps14 [60]. Additionally, some studies have demonstrated that AAV-IE-mediated upregulation of Espin can optimize stereocilia development in Atoh1-induced cochlear hair cells [61]. lncRNAs have a wide range of important functions in cellular regeneration and tissue development. It regulates these processes through various mechanisms, including chromatin remodeling, transcriptional and translational regulation, and cell cycle modulation.

lncRNA regulates ESC pluripotency and participates in embryonic development

The regulation of stem cell pluripotency has always been a focal point in life sciences. Researchers have identified a plethora of pivotal factors involved in regulating this process, including signaling pathways, TFs, and epigenetic regulators. The Wnt, Notch, and FGF signaling pathways have been shown to exert a significant influence on stem cell pluripotency regulation. Researchers have discovered that structurally tunable reduced substrates preserves the pluripotency of mouse ESCs [70], and that two-dimensional Ti3C2TxMXene combined with electrical stimulation enhances the proliferation of neural stem cells [71]. Further investigation of ESC TFs and their lncRNA targets have the potential to enhance our understanding of stem cell genomic regulatory networks, thereby facilitating rational therapeutic interventions based on the regulatory capacity of ESC lncRNAs.

lncRNA regulates tumor cell stemness

lncRNAs participate in the regulation of stemness, thereby contributing to the proliferation, migration, invasion, and metastasis of diverse tumor cells.

HOX antisense intergenic RNA (HOTAIR), a lncRNA spanning 2158 kb, is located within the HOXC locus [85]. Its mechanism involves recruiting PRC2 to specific target genes across the genome, resulting in H3K27 trimethylation and subsequent epigenetic silencing of metastasis suppressor genes [7]. HOTAIR expression is significantly upregulated in primary breast cancer and breast cancer metastases [86]. HOTAIR facilitates the invasion capability of breast cancer cells by targeting CHST15 (GalNAc4S-6ST), a chondroitin sulfate transferase, leading to chondroitin sulfate expression upregulation in glycosaminoglycan metabolism on the cell surface. Simultaneously, the HOTAIR-CHST15 axis sustains the stemness of cancer cells and promotes tumorigenesis and metastasis of breast cancer cells to lung xenografts [86]. H19 was initially characterized as a tumor suppressor factor [87]. H19 serves as a major downstream target of c-Myc and activated by c-Myc to directly bind to E-boxes proximal to the imprinting control region, thereby facilitating the recruitment of histone acetylation to the promoter region of H19 and subsequently promoting its transcriptional activation [88]. H19 is involved in essential functions during the normal development of mammary glands and in pathological mechanisms [89]. In breast adenocarcinoma, there is an overall upregulation of H19 gene expression compared to healthy tissues [90]. Overexpression of H19 is significantly correlate with tumor malignancy and the presence of estrogen and progesterone receptors [90].

HOTAIR is highly expressed in pancreatic cancer cells, with higher expression observed in advanced tumors [22]. In pancreatic cancer cells, HOTAIR interacts with polycomb repressive complex 2, comprising EZH2, SUZ12, and EED proteins to enhance the trimethylation of histone H3 at lysine 27, thereby synergistically inhibiting the growth inhibitory/apoptotic gene GDF15 alongside PRC2 [22].

MALAT-1 plays a crucial role in cancer development by promoting cell proliferation and inhibiting apoptosis [91]. Its expression is notably high in the lung, pancreatic, and non-small cell lung cancers. Moreover, MALAT-1 expression is several times higher in metastatic adenocarcinoma than in non-metastatic adenocarcinoma and serves as a strong predictor of poor prognosis in early stage disease [92]. In proto-oncogene-induced mouse hepatocellular carcinoma (HCC) nodules and human HCC samples, MALAT-1 expression was significantly increased compared to that in unaffected liver tissue [93]. HOTAIR is significantly overexpressed in tumor samples obtained from patients with HCC. Elevated HOTAIR expression is associated with an increased risk of HCC recurrence and lymph node metastasis following hepatectomy, and directly correlates with long-term patient survival [23]. Deletion of HOTAIR leads to downregulation of matrix metalloproteinase-9 and vascular endothelial growth factor proteins, which are crucial players in tumor progression [23].

HOTAIR is highly expressed in human non-small cell lung cancer and promotes aggressive behavior. Increased HOTAIR expression is frequently observed in patients with advanced lung cancer, lymph node metastasis, lymphatic vessel invasion, and shorter disease-free intervals. Moreover, compared with primary cancer tissues, brain metastases display significantly elevated levels of HOTAIR expression [24]. There is general upregulation of HOTAIR and type I collagen (Col-1) expression in human non-small cell lung cancer. The upregulation of Col-1 regulates the promoter activity of HOTAIR and triggers its transcriptional activation [94]. In the pathogenesis of Wilms’ tumor, the imprinted gene H19 located at 11p15 exhibits loss of imprinting (LOI), and in the context of lung cancer development, hypomethylation in the promoter region of H19 leads to LOI and subsequent overexpression of H19 [95]. The expression is significantly higher in H19 lung cancer tissues than in adjacent normal tissues [96]. MiR-200a expression decreases significantly with increasing tissue malignancy. Acting as a sponge RNA molecule, H19 sequesters miR-200a and inhibits its function, consequently upregulating the expression of miR-200a target genes, ZEB1 and ZEB2, while promoting epithelial mesenchymal transition (EMT) [96].

The lncRNA Taurine Up-regulated Gene 1 (TUG1) is a spliced polyadenylated transcript approximately 6.7 kb in length, which is upregulated in developing retinal cells upon taurine stimulation to actively participate in photoreceptor formation [97]. It can be induced by p53 to interact with PRC2 and exert inhibitory effects on specific genes involved in cell cycle regulation [98]. TUG1 is upregulated in bladder cancer and promotes its pathogenesis [99], whereas miR-140-3p is downregulated and inhibits tumor function. TUG1 acts as a sponge for miR-140-3p to inhibit Annexin A8 3’UTR targeting, thereby promoting progression and metastasis of bladder cancer. The expression of lncRNA UCA1 is elevated in bladder cancer tissues and promotes tumor invasion, indicating its potential as a carcinoembryonic gene [25]. Its spatiotemporal expression pattern resembles that of ncRNA H19 [100]. Moreover, UCA1 regulated the proliferation of BLS 211 cells, enhanced sustained tumor growth, and augmenteds tumorigenicity in nude mice [25]. In osteosarcoma, lncRNA TUSC7 (LOC285194) and LINC00901 (BC040587) are located within frequently altered genomic regions associated with osteosarcoma. TUSC7 deletion enhances the proliferation of normal osteoblasts by regulating apoptosis and cell cycle-related genes [101]. Both TUG1 and one of its transcript variants (n377360) exhibit significantly elevated expression levels in osteosarcoma tissues compared to adjacent normal tissues [102].

H19, STAT3, and EZH2 are highly expressed in malignant esophageal cancer (EC) cell lines. H19 knockout suppresses cell proliferation, migration, invasion, EMT, and metastasis in EC cell lines, and induces apoptosis [16]. Functionally acting as a ceRNA, H19 exerts its inhibitory role by sequestering let-7c in EC cell lines, thereby upregulating the expression of STAT3 and its downstream molecules, including EZH2, SOX4, and β-catenin.

In gastric cancer cells, miR-675 acts as a negative regulator by targeting the tumor suppressor gene runt-domain TF 1 (RUNX1), thereby mediating H19-induced progression of gastric cancer [17]. The proliferation of gastric cancer cells is regulated by the H19/miR-675/RUNX1 signaling pathway.

lncRNA loc285194, also known as LSAMP antisense RNA 3, is a tumor suppressor transcriptionally regulated by the p53 protein. Located at osteo3q13.31 and spanning >2 kb in length [101], loc285194 is downregulated in colon cancer. In this context, p53 directly targets the putative p53 response element located upstream of loc285194 to inhibit tumor cell growth. Mechanistically, loc285194 exerts its tumor-suppressive function through specific inhibition of miR-211 activity via an RNA-induced silencing complex [103].

The expression of H19 varies in normal, hyperplastic, and cancerous endometria. In the normal endometrium, H19 is exclusively expressed in the stromal cells. Within the stromal cell population, the frequency of H19 expression decreased with increasing differentiation levels. The lowest frequency of H19 expression was observed in cancerous endometrial stromal cells [104]. The expression of H19 decreases significantly with the progression of cervical cancer, which can be attributed to excessive methylation of the H19 promoter, leading to frequent down-regulation [105].

Conclusion

lncRNAs play a pivotal role in cellular development, encompassing the regulation of cell differentiation and regeneration through modulation of gene expression. They are also crucial for maintaining and regulating cellular stemness, facilitating self-renewal, and preserving the undifferentiated state to ensure tissue and organ development and repair. The regulatory mechanisms employed by lncRNAs involve various processes, including binding to chromatin to form chromatin loops that influence chromatin structure and histone modifications; interaction with TFs or other RNA molecules to affect their function and stability; and modulation of cell cycle progression, apoptosis, and other related pathways during cell differentiation and regeneration. Moreover, lncRNAs have been shown to significantly contribute to the maintenance of cellular stemness by promoting self-renewal and inhibiting differentiation, whereas they can enhance stemness by facilitating differentiation induction and self-renewal promotion. In cancer cells, lncRNAs specifically regulate stemness through diverse mechanisms, such as modulating key processes, including cell cycle progression, fate determination, and apoptosis. lncRNA can also influence metabolic activities and signaling pathways. Therefore, a comprehensive understanding of the intricate mechanism underlying the regulation of cancer cell stemness by lncRNAs will provide valuable insights into cancer initiation and progression, and offer novel perspectives for effective therapeutic strategies.

Acknowledgements

References