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Munger, K. Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/20072 (accessed on 18 December 2025).
Munger K. Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/20072. Accessed December 18, 2025.
Munger, Karl. "Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis" Encyclopedia, https://encyclopedia.pub/entry/20072 (accessed December 18, 2025).
Munger, K. (2022, March 01). Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis. In Encyclopedia. https://encyclopedia.pub/entry/20072
Munger, Karl. "Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis." Encyclopedia. Web. 01 March, 2022.
Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis
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This entry is adapted from the peer-reviewed paper 10.3390/pathogens9040289

Papillomaviruses are a large family of non-enveloped viruses with ~8000 base pair, circular, double stranded DNA genomes. They have been detected in almost all vertebrates, are highly host-specific and preferentially infect squamous epithelial tissues. Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities and they function by binding to cellular regulatory molecules, thereby subverting normal cellular homeostasis. Much effort has focused on identifying protein targets of the E6 and E7 proteins, but it has been estimated that ~98% of the human transcriptome does not encode proteins. Long noncoding RNAs (lncRNAs) are defined as transcripts of >200 nucleotides with no or limited coding potential of <100 amino acids. There is a growing interest in studying noncoding RNAs as biochemical targets and biological mediators of human papillomavirus (HPV) E6/E7 oncogenic activities.

human papillomavirus viral oncogenesis cervical carcinoma lncRNA E6 E7

1. Human Papillomaviruses as Oncogenic Drivers

Papillomaviruses are a large family of non-enveloped viruses with ~8000 base pair, circular, double-stranded DNA genomes. They have been detected in almost all vertebrates, are highly host-specific, and preferentially infect squamous epithelial tissues. More than 440 human papillomaviruses (HPVs) have been molecularly characterized as of 03/2020, and they are organized into five phylogenetic genera: alpha, beta, gamma, mu, and nu [1]. HPVs exhibit a marked preference for infecting specific squamous epithelial tissue types; most alpha HPVs infect mucosal epithelia, whereas beta, gamma, mu, and nu HPVs preferentially infect cutaneous epithelia. HPV infections are either asymptomatic or cause the formation of generally benign hyperplastic lesions, commonly referred to as warts. Some cutaneous HPV infections contribute to the initiation of cutaneous squamous cell carcinomas, particularly in long-term immunosuppressed organ transplant patients, and in individuals with a rare hereditary skin disease, epidermodysplasia verruciformis [2][3]. The mucosal alpha HPVs can be clinically classified into low and high-risk types. Low-risk HPVs cause benign genital warts, whereas high-risk HPVs cause premalignant lesions that can progress to carcinomas. Approximately 5% of all human cancers are caused by high-risk HPV infections. These include almost all cervical carcinomas, a large fraction of other anogenital tract carcinomas, and a growing percentage of oral cancers, particularly oropharyngeal carcinomas [4].
High-risk HPV-associated cancers are generally non-productive infections and only two viral genes, E6 and E7, are consistently expressed. HPV E6 and E7 encode low molecular weight, cysteine-rich, zinc-binding proteins of ~150 and ~100 amino acids, respectively. Despite their diminutive size, they are potent oncogenic drivers and are necessary for tumor initiation, progression, and maintenance. They lack intrinsic enzymatic activities and do not directly bind to specific DNA sequences. Hence, they function by binding to host cellular regulatory molecules, thereby subverting their normal physiological activities [5][6]. As a consequence, HPV E6 and E7 target almost all cellular processes that have been designated “hallmarks of cancer” [7][8]. A large number of cellular protein interaction targets for E6 and E7 have been identified, most prominently the TP53 and retinoblastoma (RB1) tumor suppressor proteins, respectively [9][10].

2. Long Noncoding RNAs

Long noncoding RNAs (lncRNAs) are defined as transcripts of >200 nucleotides with no or limited coding potential of <100 amino acids. Large intergenic noncoding RNAs (lincRNAs) are a subset of lncRNAs that do not overlap with protein-coding genes, whereas other lncRNAs share some overlap, either on the sense or antisense strand, with coding genes [11]. The first cellular lncRNAs, H19 and X-Inactive Specific Transcript (XIST), were discovered in the early 1990s [12][13]. With the development of high-throughput sequencing techniques in the late 2000s, there was a substantial increase in identified lncRNAs. Compared to the ~21,000 protein-coding genes, the number of lncRNA genes has been estimated to be in the range of ~15,000 to ~58,000 [14][15]. As sequencing depth increases, it is expected that additional lncRNAs will be identified. The majority of lncRNAs are transcribed by RNA Polymerase II, have 5′ cap structures, and are 3′ polyadenylated, rendering them biochemically indistinguishable from mRNAs. LncRNAs can localize to nuclear as well as cytoplasmic compartments.
Only ~20% of lncRNA nucleic acid sequences are significantly conserved between humans and mice, whereas the remaining lncRNAs only share small areas of microhomology [16]. The fact that such microhomologies are significant has been impressively demonstrated by complementation experiments. For example, despite limited sequence similarity of the linc-birc6 (megamind) and linc-oip5 (cyrano) lncRNAs across species, the phenotype of megamind and cyrano depletion in zebrafish was rescued by expression of murine or human transgenes [17].
LncRNAs can interact with linear RNA or DNA sequences by base pairing. Moreover, secondary and tertiary lncRNA structures can also act as recognition surfaces for binding proteins with high affinity and specificity. Molecular interactions with RNA, DNA and proteins furnish almost endless possibilities for lncRNAs modes of action. These include epigenetic regulation of gene expression, forming scaffolds for macromolecular complex assembly, binding, and inactivation of miRNAs (“sponging”), and regulating mRNA stability (Figure 1).
Figure 1. Major mechanisms of action of long noncoding RNAs (lncRNAs). See text for detail.
The role of nuclear lncRNAs in epigenetic regulation has been extensively investigated, and there are numerous examples of lncRNAs affecting the epigenetic status of neighboring loci (in cis) or at distant loci (in trans). A classic example of a lncRNA acting in cis is the X-inactive specific transcript (XIST). During X-inactivation, XIST accumulates in cis where it tethers polycomb repressive complexes to silence genes on the X-chromosome, a phenomenon referred to as X-inactivation [18]. The HOX transcript antisense intergenic RNA (HOTAIR), transcribed from the HOXC locus, acts in trans by guiding chromatin repressive complexes to HOXD and other chromosomal loci [19]. Other lncRNAs such as the HOXA transcript at the distal tip (HOTTIP) and nettoie Salmonella pas Theiler’s (NeST) cause activation of target genes by recruiting WDR5, a component of the MLL/MLL1 histone H3 lysine 4 methyltransferase complex, which marks genes for transcriptional activation [20][21].
The ability of nuclear or cytoplasmic lncRNA to associate with proteins allows them to function as scaffolds for the assembly of individual proteins into functional complexes. The nuclear enriched abundant transcript 1 (NEAT1) lncRNA, for example, forms a complex with the HEXIM1 protein to assemble a complex that contains DNAPK, cGAS, TBK1 and IRF3, which is necessary to trigger innate immune signaling in response to cytoplasmic DNA sensing [22].
Cytoplasmic lncRNAs have also been reported to act as “miRNA sponges”. By base pairing with individual microRNAs they can restrain their abilities to bind to and inhibit their mRNA targets, thereby interfering with miRNA mediated repression [23].
Lastly, cytoplasmic lncRNAs can directly or indirectly bind mRNAs thereby modulating their stability and/or translation. The pro-differentiation terminal differentiation-induced lncRNA (TINCR), for example, binds and stabilizes mRNAs that are critical for epithelial differentiation through the recruitment of the Staufen RNA binding protein [24].
Given the versatility of their biochemical modes of action, it comes as no surprise that cellular lncRNA expression is dysregulated in many cancers. However, there have been only very few studies that have carefully evaluated how specific, well-established oncogenic drivers trigger dysregulation of lncRNA expression and how this may contribute to carcinogenesis. Given that HPV E6 and E7 are universal drivers of ~5% of human cancers, they are ideally suited to address this critical matter.

3. Deregulation of lncRNAs in Cervical Carcinomas

There have been numerous studies reporting increased (Table 1) or decreased (Table 2) expression of specific lncRNAs in HPV-associated premalignant lesions and cancers (see tables below for references). By proposing specific mechanisms of action and linking aberrant expression to specific oncogenic phenotypes, these studies suggest that dysregulated lncRNA expression may importantly contribute to HPV carcinogenesis by subverting cellular processes that have been referred to as “hallmarks of cancer” [7][25].
Table 1. lncRNAs reported to be upregulated in various models of cervical lesions and cancers.

lncRNA

Oncogenic Phenotype

Proposed Mechanism

References

ANRIL

Proliferation, migration, invasion

PI3K/AKT; Cyclin D1, CDK4, CDK6, N-cadherin, Vimentin expression

[26][27]

ARAP1-AS1

Proliferation, invasion

MYC translation by PSF/PTB

[28]

BLACAT1

Proliferation, migration, invasion

WNT signaling/β-catenin

[29]

CCAT2

Proliferation, apoptosis

None reported

[30]

CCEPR (CCHE1)

Proliferation

PCNA mRNA stabilization

[31]
 

Proliferation

independent of PCNA mRNA

[32]

CRNDE

Proliferation, migration, invasion

miR-183 sponging/cyclin B1

[33]
 

Proliferation

PUMA expression

[34]

DANCR

Proliferation, migration, invasion

miR-665 sponging/TGFβ-R1-ERK-SMAD

[35]
 

Proliferation, migration, invasion, epithelial to mesenchymal transition (EMT)

miR-335-5p sponging/ROCK1

[36]

EBIC (TMPOP2)

Motility, invasion

E-cadherin silencing by EZH2

[37]
 

Proliferation

miR-375, miR-139 sponging

HPV E6/E7 expression

[38]

FAM83H-AS1

Proliferation, migration and apoptosis

G1/S-phase transition

[39]

GATA6-AS

Migration, invasion

MTK-1

[40]

H19

Proliferation, anchorage independent growth

None reported

[41]

HOTAIR

Apoptosis, invasion, migration

NOTCH signaling

[42]
 

Apoptosis, proliferation, invasion

miR-23b sponging/MAPK1 axis

[43]
 

Autophagy, EMT

WNT signaling

[44]
 

Proliferation

miR-143-3p sponging/BCL2

[45]

HOXD-AS1

Proliferation

Ras/ERK

[46]

Linc00483

Proliferation, apoptosis, invasion, migration

miR-508-3p sponging/RGS17

[47]

LINP1

DNA damage repair (Non-homologous end joining)

KU80, DNA-PKcs binding

[48]

Lnc-IL7R

Apoptosis

BCL2/caspase 3

[49]

LUCAT1

Proliferation, migration, invasion

miR-181a sponging

[50]

MALAT1

Cell invasion and metastasis

inhibition of EMT genes

[51]
 

Proliferation, migration, invasion

miR-625-5p/AKT2

[52]
 

Proliferation

Mir-625-5p/NF-kB signaling

[53]
 

Cisplatin resistance

PI3K/AKT

[54]

MIR205HG

Proliferation, apoptosis, migration

SRSF1/KRT17 axis

[55]

NEAT1

Proliferation, invasion

PI3K/AKT

[56][57]
 

Colony formation, migration, invasion

miR-133a sponging/SOX4

[58]

NORAD

Proliferation, invasion

miR-590-3p sponging/SIP1

[59]

PANDAR

Proliferation

None reported

[60]

PVT1

Proliferation, invasion

Inhibiting TGFβ;

miR-140-5p sponging/SMAD3

[61][62]
 

EMT, chemoresistance

miR-195 epigenetic silencing

[63]

SNHG8

Proliferation, apoptosis

RECK silencing by EZH2

[64]

SNHG12

Proliferation, apoptosis

ERK/Slug

[65]

SNHG16

Proliferation, invasion

PARP9 expression by SPI1 binding

[66]

TUG1

Proliferation, apoptosis, invasion, tumor growth

miR-138-5p sponging/SIRT1

[67]
 

Proliferation, apoptosis, EMT

BCL-2, caspase 3; fibronectin, vimentin, and cytokeratin

[68]

TP73-AS1

Proliferation, migration

miR-329-3p sponging/SMAD2

[69]
 

Proliferation, migration, invasion

miR-607 sponging/CCND2

[70]

UCA1

Radioresistance

HK2/glycolytic pathway

[71]

XIST

Proliferation

miR-140-5p sponging/ORC1

[72]
 

Proliferation, invasion, apoptosis, EMT

miR-200a sponging/FUS

[73]

ZEB-AS1

Proliferation, migration, invasion, EMT

ZEB1 expression

[74]
Table 2. lncRNAs reported to be downregulated in various models of cervical lesions and cancers.

lncRNA

Oncogenic Phenotype

Proposed Mechanism

Reference

GAS5

Proliferation, invasion, migration

E-cadherin, Vimentin

[75]
 

Proliferation, migration, invasion, colony formation

miR-21 expression/STAT3

[76]
 

Radiosensitivity

miR-106b sponging/IER3

[77]

HOTAIR

Decreased polycomb repression

Binding to HPV E7

[78]

Lnc-CCDST

Migration, invasion, angiogenesis

DHX9, MDM2 scaffolding

[79]

MEG3

Proliferation, apoptosis

Binding, degradation of P-STAT3

[80]
 

Proliferation, colony formation, apoptosis

miR-21-5p expression/TP53

[81]

STXBP5-AS1

Viability, invasion

miR-96-5p expression/PTEN

[82]

TINCR

Differentiation, colony formation, migration

S100A8 and other ZNF750 targets

[83]

WT1-AS

Proliferation

TP53

[84]
 

Proliferation, invasion, migration

miR-203a-5p binding/FOXN2

[85]

XLOC_010588

Proliferation

MYC mRNA binding/degradation

[86]

4. Deregulation of lncRNAs by HPV E6 and/or E7 Proteins

Several reviews have focused on the clinical implications of lncRNA expression changes in HPV-associated cancers [87][88][89], but dysregulation of cellular lncRNA expression in HPV-associated lesions and cancers does not infer that the observed changes represent a primary consequence of HPV infection and E6 and/or E7 expression. Some of the studies cited in the tables above implicated E6 and/or E7 as regulators of certain lncRNAs, including PVT1, MALAT1, SNHG12, lnc-CCDST, LINC01101, and LINC00277 [63][65][79][90][91] by depleting E6/E7 expression in cervical cancer lines.
To determine how HPV16 E6/E7 expression deregulates lncRNA expression in normal human epithelial cells, the researchers analyzed RNA sequencing (RNAseq) data of two independently derived populations of HPV16 E6/E7 expressing primary human foreskin keratinocytes (HFKs) and their donor and passage matched, control vector-transduced parental cells [92]. Of the 7109 annotated lncRNA species that were detectably expressed, the levels of 1453 were altered at least twofold. Of these, 1070 lncRNAs were expressed at higher levels whereas 383 were expressed at lower levels in HPV16 E6/E7 expressing HFKs than in parental HFKs (Figure 2A).
Figure 2. Differential expression of cellular lncRNAs in human papillomavirus (HPV)16 E6/E7 expressing human foreskin keratinocytes (HFKs). (A). Expression of annotated cellular lncRNA by RNA sequencing (RNAseq) analysis of HPV16 E6/E7 expressing and parental primary HFKs. (B). Quantitative reverse transcription PCR (qRT-PCR) analysis of select cellular lncRNAs in HPV16 E6/E7 expressing versus parental HFKs. See text for detail.
From this list, the researchers analyzed by quantitative reverse transcription PCR (qRT-PCR), expression of a small number of lncRNAs that were shown to be dysregulated in HPV-associated lesions and cancers (see Table 1; Table 2) or are well-established modulators of cancer hallmarks targeted by HPV16 E6/E7. From this panel, the most significantly upregulated and downregulated lncRNAs are the cervical carcinoma expressed PCNA regulatory lncRNA (CCEPR) and the DNA damage-induced noncoding lncRNA (DINO), respectively. HOTAIR, human ovarian cancer-specific transcript 2 (HOST2), growth arrest-specific 5 (GAS5), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and tissue differentiation-inducing non-protein coding RNA (TINCR) were downregulated, whereas hepatocellular carcinoma up-regulated EZH2-associated lncRNA (HEIH), differentiation antagonizing non-protein coding RNA (DANCR), EZH2-binding lncRNA in cervical cancer (EBIC), neuroblastoma associated transcript 1 (NBAT1) and H19 were upregulated in HPV16 E6/E7 expressing HFKs (Figure 2B).

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