LncRNAs are regulatory transcripts longer than 200 nucleotides in length ^[1][9]. Numerous lncRNAs regulate the transcription of nearby genes, DNA repair, and the response to DNA damage, while some are involved in regulatory and structural functions, including splicing, epigenetics, signaling pathways as well as turnover and translation of mRNA ^[1][2][3][9,21,23]. lncRNA are thought to regulate downstream genes via competitively binding to miRNA at the post-transcriptional level; for instance, HOTAIR can control the miR-143-3p/BCL2 and miR-20a-5p/HMGA2 axis promoting cell growth and metastasis ^[4][26]. Li et al. ^[5][59] revealed an interaction between lncRNA SNHG4, c-Met, and miR-148a-3p, where SNHG4 upregulated c-Met through targeting miR-148a-3p and promoted cervical cancer development. In HPV 16 positive cervical cancer, Growth factor receptor-bound protein 2 (GRB2), responsible for cell communication, is highly expressed. MALAT1 is reported to indirectly influence GRB2 expression by interacting with miR-124 ^[6][55]. Several other ceRNA regulatory axes promote cervical cancer have been reported, as shown in Table 1.

Table 1. CeRNA regulatory axis in cervical cancer.

ceRNA	Regulatory Axis	Role in Cervical Cancer	Ref
circRNA 400029	miR-1285-3p/TLN1	Aggressive behaviors of cervical cancer	[7][44]
circCLK3	MiR-320a/Fox M1	Cervical cancer progression	[8][43]
hsa_circ_0001038	miR-337-3p/cyclin-M3	Promotes cell growth, migration, and invasion	[9][45]
hsa_circRNA_101996	miR-8075/TPX2	Promotes cell growth and invasion	[9][45]
hsa_circ_0023404	miR-136/TFCP2	Cervical cancer development and progression	[10][25]
circ-EIF4G2	miR-218/HOXA1	Modulates malignant biological behaviors	[11][46]
Hsa_circ_0000301	miR-1228-3p/IRF4	Cancer progression	[12][47]
miR-532-5p	LINC01410/FASN	Tumour metastasis	[13][48]
LncRNA XIST	miR-200a/Fus	Cancer progression	[8][43]
LncRNA XIST	miR-140-5p/ORC1	Cell proliferation and increased expression of Bcl-2	[14][49]
LncRNA HOTAIR	miR-206/MKL1	Migration and invasion	[15][50]
LncRNA HOTAIR	miR-143-3p/BCL2	Inhibit tumor suppression	[16][51]
LncRNA HOTAIR	miR-148a/human leucocyteantigen-G (HLA-G)	Proliferation, migration, and invasion of cervical cancer cells	[17][52]
LncRNA NEAT1	miR-133a/Sox4	Cell proliferation, migration, and invasion	[18][53]
LncRNA LINC01128	miR-383-5p/SFN	Inhibits apoptosisproliferation, migration, and invasion of cervical cancer cells	[19][54]
LncRNA MALAT1	miR-124/RBG2	Proliferation, migration, and invasion	[6][55]
lncRNA OIP5-AS1	miR-143-3p/ROCK1	Inhibit apoptosis and promotes cell proliferation	[20][56]
LncRNA RNA POU3F3	miR-127-5p/FOXD1	Promoted the proliferation and invasion	[21][57]
LncRNA RP11-552M11.4	miR-3941/ATF1	Cell proliferation	[22][58]
SNHG4	miR-148a-3p/c-Met	Improve cell viability and inhibit apoptosis	[5][59]
SNHG12	miR-125b/STAT3	Proliferation and invasion of cervical cancer	[5][59]
lncRNA SU1P2	let-7a/IGF1R, let-7a/N-myc, and let-7a/EphA4	Promotes tumorigenesis	[6][55]
LncRNA SNHG20	miR-140-5p-ADAM10	Promote cervical cancer cells proliferation and invasion	[23][60]
ZNF667-AS1	microRNA-93-3p/PEG3	Decreases tumor invasion and metastasis	[24][61]

LncRNAs play an essential role in regulating alternative splicing. LncRNAs influence alternative splicing by interacting with splicing factors. However, they can hijack splicing factors, causing dysregulation of alternative splicing. For example, Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is excessively expressed in cancer tissues and cervical cancer cells infected with “high risk” HPV ^[25][64], interacts with several serine-arginine proteins, namely SRSF1, SRSF2, SRSF3 and SRSF5 ^[26][65]. MALAT1 regulates serine-arginine proteins’ phosphorylation/dephosphorylation ratio, thus affecting their transportation and distribution to transcription sites and between nuclear speckle domains ^[9][26][45,65]. The mechanism for the phosphorylation of serine proteins by MALAT1 is still unclear; however, it might happen via interaction with PP1/2A phosphatases ^[27][66]. Studies demonstrate that MALAT1 can upregulate SRSF1-mediated splicing events that promote carcinogenesis (e.g., angiogenesis) ^[28][67]. In CaSki (HPV 16+) cervical cancer cells, MALAT1 encourages cell proliferation, migration, and cell cycle progression ^[29][68]. Other lncRNAs, such as MIR205HG, promote cervical cancer progression by targeting SRSF1 and regulating KRT17 ^[30][69].

LncRNAs can drive alternative splicing by interacting with cis-acting elements in pre-mRNA via RNA-RNA base pairing ^[2][21]. Interactions of the lncRNA (Saf) with cis-acting elements have been shown to promote exon skipping of Fas 6 through the recruitment of SPF45 to Fas pre-mRNA, causing the expression of soluble Fas. Soluble Fas promotes cancer progression by impeding Fas-FasL moderated apoptosis in numerous cancers, including cervical cancer ^[2][26][21,65].

miRNAs are a type of single-stranded RNA that is 20–22 nucleotides long and regulates gene expression by binding to sequence motifs found in the three ′ untranslated regions (UTR) of mRNA transcripts ^[3][31][32][22,23,70]. MiRNAs play a pivotal role in influencing gene expression and the development and growth of tumors ^[33][71]. Free circulating miRNAs are sponged by lncRNAs and circRNA, preventing them from interfering with transcription and obtaining the goal of gene expression ^[12][47]. Most often, miRNAs are tumour suppressers that target mRNAs that encode viral proteins and are involved in altered molecular functions in tumors ^[13][48]. MiR-124, a tumor suppressor, is reportedly low in cervical cancer due to being sponged up by MALAT1. The sponging up of miR-124 causes the upregulation of RBG2, resulting in cancer proliferation and invasion ^[6][55]. Many other miRNA including miR-1285-3p, miR-320a/, miR-337-3p, miR-8075, miR-136, miR-218, miR-1228-3p, miR-532-5p, miR-200a, miR-140-5p, miR-206, miR-143-3p, miR-148a, miR-383-5p, miR-143-3p, miR-127-5p, miR-3941, miR-148a-3p, miR-125b, miR-140-5p and microRNA-93 are sponged by lncRNA, and circRNA thus promoting cervical cancer development, invasion and metastasis, as shown in Table 1. Shang et al. 2022 ^[13][48] revealed downregulation of miR-532-5p, resulting in nodal metastasis.

Studies have reported on the role of miRNAs in alternative splicing ^[2][34][21,62]. MiRNAs can regulate alternative splicing in multiple ways. Other miRNA functions as NATs, causing aberrant splice site selection in cancer. miRNAs also rearrange chromatin structure, affecting splicing factor recruitment, interact with Polymerase III, and influence histone modification and DNA methylation ^[34][62].

miRNAs are involved in regulating the expression of splicing factors. Splicing Factor expression can be inhibited by miRNAs through complete or partial complementarity to the target sequences of mRNA coding for SFs, leading to mRNA degeneration or translation downregulation ^[2][21]. Multiple miRNA-related influences on splicing factors have been discovered in many cancers, including cervical cancer. MiR-7, for example, inhibits SF SRSF1 mRNA translation in HeLa cells via partial complementarity with its 3’UTR, suppressing cancer cell survival. MiR-221, miR-222, and miR-17-92 are also known to influence SRSF1. SRSF1 is involved in the expression of various cancer-promoting genes, including pro-apoptotic Bcl-x, R.O.N., and MCL-1 isoforms ^[34][62] and activating SRSF1 through its kinase SRPK1 is activated by HPCV infection ^[35][72]. MiR-802 is shown to target SRSF9 and cause apoptosis in cervical cancer ^[36][73]. CircRNAs and lncRNAs have increased SF expression in cancers, including cervical cancer, by regulating alternative splicing ^[2][21].

There is a growing concern among researchers on the role played by circRNA in cancer, including cervical cancer ^[37][74]. Studies have implicated circRNAs in cervical cancer development, aggression and progression not only through deregulating chromatin modifications but additionally through competitively binding to miRNA to regulate the expression of genes ^[7][44]. CircRNA such as circRNA_400029 and circEPSTI1 promote cancer growth, invasion and inhibits cell death via regulating the miR-1285-3p/TLN1 and miR-375/409-3P/515-5p-SLC7A11 axis, respectively ^[7][37][44,74]. CircSLC26A4 encourages cervical cancer growth by regulating the miR-1287-5p/HOXA7 axis ^[37][74]. These studies suggest that circRNAs regulate cancer development and progression through downregulating miRNAs. Song et al. 2020 ^[38][75], revealed that circRNA-101996 downregulates miR-8075 and upregulates TPX2 expression. Furthermore, it was suggested that a single circRNA could sponge several miRNAs. For example, circRNA_101996 could sponge miR-8075 and miR-1236-3p. Various other circRNA have been shown to play a regulatory role in cervical cancer, as shown in Table 1.

The functions of circRNA are unknown; however, studies have shown that they are generated through back splicing of mRNA ^[39][76]. CircRNAs play a critical role in regulating alternative splicing. Furthermore, circRNA can enlist or inhibit particular proteins from acting as scaffolds to aid protein-enzyme reactions. circRNA have been observed to encourage splicing Factor expression by sponging miRNAs, thus regulating alternative splicing in malignancies ^[2][21]. Moreover, circRNA are involved in RNA splicing and mRNA by acting as a sponge for ribonucleoprotein ^[40][77]. It has been observed in glioblastoma multiforme that circRNAs like circRNA cir-c SMARCA5 are able to regulate the expression of VEGF-Axxxa pre-mRNA through binding to the SF SRSF1 ^[2][21]. However, there is limited literature on the involvement of circRNAs in alternative splicing in cervical cancer.

PRMTs are overexpressed in several cancers, including cervical cancer ^[15][41][42][50,78,79]. Alternative splicing of PRMT genes produces novel circRNAs implicated in several cancers, for example, splicing of the PRMT1 gene in breast cancer ^[43][80] and circPRMT5 in non-small cell lung cancer and bladder cancer ^[44][81]. Functional cooperation exists between PRMTs and ncRNAs resulting in a net upregulation of PRMTs in cancers ^[45][82].

Small RNA expression profiling in cervical neoplasia revealed upregulated “oncogenic” miRNAs like miR-19, miR-146a, miR-21, and miR-10a, as well as down-regulated “tumor-suppressive” miRNAs like miR-29a, miR-218, miR-214, and miR-372, which are involved in cell proliferation, neoplastic transformation, cell migration, and invasion ^[31][22]. The HPV genome encodes the HPV-16-miR-H1-1 and HPV-16-miR-H2-1, capable of targeting essential cell genes such as those governing cell cycle progression, migration, and immune response, in addition to being required for viral infection and upkeep ^[46][83].

LncRNAs can bind mRNAs, proteins, or miRNAs and are entangled in several biological functions. The deregulation of lncRNA expression has been linked to cardiovascular and neurodegenerative diseases and cancer development. Multiple lncRNAs such as HOTAIR, H19, MALAT1, CCAT2, SPRY4-IT1, GAS5, CCHE1, MEG3, LET, EBIC and PVT1 are thought to play essential roles in cervical cancer growth, invasion and metastasis, and radio-resistance ^[31][22]. CircRNAs, like lncRNA, act as a sponge for miRNA competing for mRNA binding. Circ-0018289 has been shown to sponge miR-497 and contribute to the dysregulation of target genes ^[31][47][22,84]. Viral agents encode for circE7, which overexpresses the E7 oncoprotein, thus driving cell transformation ^[31][22]. The generation of lncRNAs is part of the process of alternative splicing of the human genome ^[26][65]. For instance, in lung adenocarcinoma, breast cancer, and colorectal adenocarcinoma, it has been observed that the splicing factor hnRNPE1 binds to the PNUTS 5′ pre-mRNA exon 12 splicing site, promoting the production of PNUT mRNA. The dissociation of hnRNPE1 induces the formation of lncRNA PNUTs isoforms, which are implicated in epithelial-to-mesenchymal transition (EMT), resulting in tumor progression. The lncRNA PNUTS acts as competitive sponges for miR-205, inhibiting miR-205 binding to the ZEB1 gene, thus causing an upregulation of ZEB1. The upregulation of ZEB1 inhibits the expression of E-cadherin, thereby inducing Epithelial-mesenchymal transitions (EMT) and tumor progression ^[26][48][65,85].