The long noncoding RNA lnc-FANCI-2 intrinsically restricts RAS signaling in human papillomavirus type 16-infected cervical cancer cells

Cervical cancer is a leading cause of mortality in women worldwide. It is the second most diagnosed cancer among women, with an estimated 661,000 new cases worldwide each year, and the third most frequent cause of cancer-related death, accounting for 348,000 deaths annually (Bray et al., 2024). Persistent infections in the cervical epithelium with the cancer-associated alpha human papillomaviruses (high-risk HPVs [HR-HPVs]), in particular HPV16 and HPV18 with the sustained expression of viral oncoproteins, E6 and E7, contribute to squamous epithelial cell tumorigenesis (Bosch et al., 2002; Munoz et al., 2003; Walboomers et al., 1999). Approximately 31.3% of high-grade neoplastic cervical lesions progress to invasive cervical cancer (ICC) in 30 years (McCredie et al., 2008), while most lesions resolve spontaneously. The progression to cervical cancer typically takes 15–20 years after initial infection (https://www.who.int/news-room/fact-sheets/detail/cervical-cancer). These observations suggest that active host defense systems play important roles in preventing malignant transformation of neoplastic cervical lesions, and additional factors besides E6 and E7 are necessary for cervical cancer development. Indeed, one tumor suppressor network, the Fanconi anemia (FA) pathway (Niraj et al., 2019), can be activated by HPV-induced DNA damage. FA proteins, including FANCA, FANCD2, and FANCI, are elevated upon HPV infection (Hoskins et al., 2009; Liu et al., 2021; Santegoets et al., 2012), and the activated FA pathway restricts HPV replication and guards host genome stability (Hoskins et al., 2012). FANCD2 mutation stimulates HPV16 and HPV31 genome amplification and also promotes cervical and vaginal cancer development in HPV16 E7 transgenic mouse (Park et al., 2010; Park et al., 2014).

HPV-positive cervical cancer tissues in general exhibit wild-type (WT) p53, WT K-RAS, and no overexpression of RAS genes (Hietanen et al., 2000; Tommasino et al., 2003; Prior et al., 2012; Fernández-Medarde and Santos, 2011). Viral oncoprotein E7 plays a major role in the immortalization of primary epithelial cells mainly by inactivation of pRb family of proteins (Roman and Munger, 2013), whereas E6 mediates degradation of tumor suppressor p53 and activation of human telomerase reverse transcriptase transcription (Vande Pol and Klingelhutz, 2013; Liu et al., 2009; Klingelhutz et al., 1996). However, high-risk E6 and E7 are necessary but not sufficient to transform fully the immortalized cells into malignant cells (Storey et al., 1988; Barbosa and Schlegel, 1989; Hawley-Nelson et al., 1989; Münger et al., 1989; Halbert et al., 1991), and additional oncogenic stress is needed. For example, the HRAS^G12V, a constitutively activated RAS GTPase mutation, triggers malignant transformation of E6/E7-expressing keratinocytes (Phelps et al., 1988; DiPaolo et al., 1989; Schreiber et al., 2004; Narisawa-Saito et al., 2008). Normal RAS regulates cell proliferation, cell differentiation, and cell adhesion through cellular signal transduction from growth factor receptors such as insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBP1–6) (Conover et al., 2000; Allard and Duan, 2018; Bach, 2018). Thus, overactive RAS signaling might facilitate transformation of E6/E7-expressing keratinocytes. In transgenic mice, HPV16 E6 and E7 can promote the development of spontaneous epithelial skin tumors, but not spontaneous tumors of the reproductive tract (Song et al., 1999; Herber et al., 1996; Song et al., 2000; Riley et al., 2003). Prolonged estrogen treatment is required (Brake and Lambert, 2005). Estrogen receptor (ER) activation stimulates the mitogen-activated protein kinase (MAPK/Erk) and phosphoinositide 3-kinase (PI3K/Akt) pathways, both of which are mediated by RAS (Kato et al., 1995). However, the molecular mechanism underlying estrogen-induced cervical cancer in E6 and E7 transgene mice is not fully understood.

Long noncoding RNAs (lncRNAs) are RNAs over 200 nucleotides (nt) in length lacking a coding capacity for translation into functional proteins. Although several lncRNAs have been proposed to function in diverse biological processes, evidence is still lacking to support the functionality of the majority of lncRNAs (Statello et al., 2021; Liu and Zheng, 2022).

We recently reported an increased level of lnc-FANCI-2 expression in high-risk HPV-positive cervical intraepithelial neoplasia (CIN) and ICC tissues (Liu et al., 2021). At least 14 RNA isoforms of lnc-FANCI-2 are expressed by usage of two alternative promoters, alternative RNA splicing, and alternative selection of two polyadenylation sites from the genomic locus adjacent to the FANCI on Chr15. Ironically, the lnc-FANCI-2 was wrongly annotated by NCBI as a MIR9-3HG in the recently updated RefSeq database (https://www.ncbi.nlm.nih.gov/refseq/) and two alternative lnc-FANCI-2 promoters identified for expression of lnc-FANCI-2 are ~10 kb downstream of the non-expressible MIR9-3 gene (Liu et al., 2021). Both lnc-FANCI-2 and FANCI are upregulated simultaneously in neoplastic cervical lesions and cervical cancer by HR-HPV infections. E6, and in particular, E7 is responsible for the enhanced expression of lnc-FANCI-2, the transcription of which is also regulated by YY1 (Liu et al., 2021). HPV infection increases YY1 levels but decreases the expression of p53-dependent miR-29a which targets the YY1 3’ UTR. Viral E7 interacts with YY1 and facilitates YY1 transactivation of lnc-FANCI-2 promoter (Liu et al., 2021). In situ hybridization has revealed that lnc-FANCI-2 is preferentially cytoplasmic, but its function in HPV-infected cells has not been characterized. In this report, we demonstrate that lnc-FANCI-2 in HPV16-infected cells controls RAS signaling by interaction with MAP4K4 and other RNA-binding proteins. Ablation of lnc-FANCI-2 in the cells promotes RAS signaling and phosphorylation of Akt and Erk. High levels of lnc-FANCI-2 and low levels of MCAM expression in cervical cancer patients correlate with improved survival, indicating that lnc-FANCI-2 plays a critical role in regulating RAS signaling to affect cervical cancer progression and patient outcomes.

HPV oncoproteins E6 and E7 are necessary but not sufficient for development of cervical cancer. Indeed, early studies indicated that other oncogenic stress, such as activated RAS mutant, is needed to trigger malignant transformation of E6- and E7-expressing cells (Storey et al., 1988; Phelps et al., 1988; Crook et al., 1988; Matlashewski et al., 1987) and tumorigenesis (DiPaolo et al., 1989; Schreiber et al., 2004; Greenhalgh et al., 1994; Riou et al., 1988; Eiben et al., 2002; Golijow et al., 1999; Prokopakis et al., 2002). Moreover, E7 has also been reported to repress phosphorylation of Akt and Akt-mediated signaling (Strickland and Vande Pol, 2016). In this study, we show that lnc-FANCI-2, whose expression is highly dependent on E7 and YY1 (Liu et al., 2021), intrinsically restricts RAS GTPase activities and phosphorylation of Akt and Erk presumably by interacting with cellular factors in HPV16-positive CaSki cells. Interestingly, early reports indicated that p-Akt attenuation by E7 could be abolished by introduction of the H73E mutation in the E7 CR3 domain (Strickland and Vande Pol, 2016). This E7 CR3 domain is also essential for interacting with transcription factor YY1 to activate lnc-FANCI-2 transcription (Liu et al., 2021). Thus, it would be presumable that the reported p-Akt attenuation by E7 might be mediated by the increased expression of lnc-FANCI-2. More importantly, these findings also suggest that additional oncogenic stress, such as activated RAS mutant, is required to overcome the lnc-FANCI-2 restriction on RAS signaling for the early observed malignant transformation (Storey et al., 1988; Phelps et al., 1988; Crook et al., 1988; Matlashewski et al., 1987) and tumorigenesis (DiPaolo et al., 1989; Schreiber et al., 2004; Greenhalgh et al., 1994; Riou et al., 1988; Eiben et al., 2002; Golijow et al., 1999; Prokopakis et al., 2002) of E6- and E7-expressing cells. In CaSki cells, loss of lnc-FANCI-2 in this report was found to promote RAS signaling but reduction of IFN responses. However, high RAS-AKT-ERK signaling induces cell senescence and inhibits tumor cell survival as shown in this report and in a lung cancer study (Nieto et al., 2017).

Some lncRNAs function as RAS regulators (Yang et al., 2019; Saliani et al., 2022) by their ability to sequester RAS-targeting miRNAs, including MALAT1/miR-217, RMRP/miR-206, and KRAS1P/miR-143/let-7 (Saliani et al., 2022). Conceivably, lncRNAs may also regulate RAS signaling through other mechanisms beyond miRNAs. In this report, loss of lnc-FANCI-2 in HPV16-positive CaSki and SiHa cells promotes RAS signaling and expression of RAS signaling effectors (Figure 9E). By profiling the proteins associated with lnc-FANCI-2 in CaSki cells, we identified a serine/threonine protein kinase MAP4K4 as one of the major lnc-FANCI-2-binding proteins that may partially mediate the lnc-FANCI-2 restriction on RAS signaling. MAP4K4 is a negative RAS signaling regulator in the context of the early embryo (Gao et al., 2017; Patterson et al., 2023) and lymphatic vascular development by interacting with RASA1 (Roth Flach et al., 2016). Indeed, silencing of MAP4K4 in parental WT CaSki cells, like KD or KO of lnc-FANCI-2, led to a partial increase of both p-Akt and p-Erk1/2 (Figure 9D) as reported (Patterson et al., 2023; Roth Flach et al., 2016). Interestingly, KD of MAP4K4 in ΔPr-A9 cells led to further increased expression of p-Erk1/2 but minimal on p-Akt (Figure 8—figure supplement 1C), suggesting a negative correlation of MAP4K4 activity in interaction with lnc-FANCI-2 on Erk1/2 phosphorylation. Thus, our data suggest that MAP4K4 protein may function in coordination with lnc-FANCI-2 RNA in CaSki cells to restrict one arm of RAS signaling, but not the other.

All HR-HPVs are capable of inducing lnc-FANCI-2 expression by experimental infection of keratinocytes (Liu et al., 2021). HPV⁺ cervical cancer tissues express high levels of lnc-FANCI-2. As expected, all HPV16⁺ cervical cancer and pre-cancer cell lines examined – such as CaSki, SiHa, W12 subclone cells 20861 (HPV16⁺, integrated) and 20863 (HPV16⁺, episomal) – produce lnc-FANCI-2. Unexpectedly, we found no expression of lnc-FANCI-2 in isogenic HPV18⁺ HeLa and C4II cells, nor in colorectal cancer cell line HCT116, adenovirus 5 DNA-transformed human embryonic kidney cell line HEK293, spontaneously transformed aneuploid immortal keratinocyte cell line HaCaT, and KSHV-infected B cell lymphoma cell line BCBL-1 cells which are all HPV-negative cell lines. It remains to know what negatively regulates lnc-FANCI-2 expression in those cell lines, and more HPV18⁺ cell lines should be examined for lnc-FANCI-2 expression. However, we did find that an HPV-negative cervical cancer cell line, C33A cells expressing mutant p53 and mutant pRB (Scheffner et al., 1991), produces a high level of lnc-FANCI-2 (Figure 2). Using dual luciferase report assays, we did find lnc-FANCI-2 promoter activity in response to YY1 binding in CaSki and C33A cells, but not in HeLa and HCT116 cells, suggesting the presence of a repressive factor(s) in the latter two cell lines (data not shown). KD of E2F1 had no effect on lnc-FANCI-2 promoter activity in CaSki cells (Liu et al., 2021). In the lnc-FANCI-2-producing cells, we noticed that the cellular location of lnc-FANCI-2 also varies from cell types, with lnc-FANCI-2 predominantly in the nucleus in SiHa and C33A cells, but in the cytoplasm in CaSki cells, although both cytoplasmic and nuclear lnc-FANCI-2 restrict RAS signaling. This suggests that a variety of nuclear and cytoplasmic functions of lnc-FANCI-2 remains to be explored.

IGFBP3 is a major IGF carrier and enhances both IGF- and EGF-RAS signaling (Allard and Duan, 2018; Martin et al., 2003) to activate phosphatidylinositol 3-kinase (PI3K)/AKT and the MAPK/ERK pathways (Józefiak et al., 2021). Surprisingly, we find a suppressive role of IGFBP3 on Erk phosphorylation, but not much on Akt, in the presence or absence of lnc-FANCI-2 in HPV16-positive CaSki cells. Although ~99% of circulating IGF-1 is bound to IGFBPs, predominantly to IGFBP-3, the most abundant IGFBP in human serum, case-control studies showed significantly lower IGF-1 and IGFBP-3 serum levels in the patients with ICC over the control group (Jozefiak et al., 2008; Serrano et al., 2006). A reduced expression of IGFBP-3 mRNA level appears to be associated with progression to cervical cancer (Serrano et al., 2007). Consistent with lnc-FANCI-2’s suppressive effect on IGFBP3 expression in our study, an increased level of lnc-FANCI-2 expression is associated step-wisely with HR-HPV-positive CIN and ICC tissues (Liu et al., 2021).

It is obvious from our RNA-seq and human soluble receptor array analysis that KO of lnc-FANCI-2 in CaSki cells affects the expression of a large set of genes, including the expression of increased NECTIN2, ADAM9, ADAM10, ITGA5, MCAM, PODXL2, ECM1, but decreased ADAM8, TIM2, and ITGB6, which are responsible for RAS signaling, EMT pathway, and IFN responses. For example, the dysregulation of RAS signaling and ADAM protein activity is implicated in various cancers. ADAM proteins can modulate RAS signaling by cleaving and releasing ligands that activate or inactivate RAS-related pathways (Schäfer et al., 2004; Ohtsu et al., 2006; Dang et al., 2011; Kleino et al., 2015). Some ADAM proteins are involved in the migration and invasion of cancer cells, and their loss can promote the degradation of KRAS (Huang et al., 2024). ADAMs are essential for extracellular signaling and regulation of cell adhesion, and their catalytic activity is strongly correlated to Src-homology 3 (SH3) domain binding of SH3 proteins (Dang et al., 2011; Kleino et al., 2015; Sun et al., 2010). In addition to the notified activation of PI3K/Akt and Raf/Mek/Erk pathways, one of the major RAS signaling effectors in lnc-FANCI-2 KO or KD cells was found to be MCAM.

MCAM binds various cellular surface receptors or co-receptors to trigger signal transduction, cell proliferation and motility, tumor angiogenesis, and tumor cell metastasis (Wang et al., 2020; Joshkon et al., 2020). It is an integral, highly glycosylated membrane protein with three common protein isoforms (Wang et al., 2020; Anfosso et al., 1998; Dye et al., 2009): two membrane-anchored forms with a long (p113) or short (p76) cytoplasmic tail produced by alternative RNA splicing and a proteolytically cleaved soluble form without transmembrane and cytoplasmic regions (Wang et al., 2020; Dye et al., 2009; Bardin et al., 1998). In addition to its roles in cell signal transduction (Wang et al., 2020; Joshkon et al., 2020; Anfosso et al., 1998; Dye et al., 2009), the short isoform produced by an intramembrane cleavage may be directed toward the nucleus to regulate gene transcription (Stalin et al., 2016). We found that CaSki cells express mainly a cytoplasmic form of full-length MCAM (~113 kDa) and a small nuclear form (~46 kDa), but not the short (~76 kDa) isoform. Moreover, lnc-FANCI-2 KO cells exhibit high MCAM levels, which was most likely a result of the increased RAS signaling. Consistently, lnc-FANCI-2 and MCAM levels are negatively correlated in cervical cancer patients, and low levels of MCAM and high levels of lnc-FANCI-2 indicate better prognosis. This suggests that increased MCAM might promote cervical tumorigenesis in vivo. Given that the cells with Inc-FANCI-2 KO exhibit increased levels of IGFBP3 and MCAM, and the ΔPr-A9 cells with rescued lnc-FANCI-2 RNA expression displayed remarkable reduction of IGFBP3 and MCAM expression, our current model (Figure 9E) highlights how the HPV16-enhanced expression of lnc-FANCI-2 in cervical cancer cells might function as a negative regulator by binding to various RNA-binding proteins to block RAS signaling and reduce the expression of RAS signaling effectors such as IGFBP3 and MCAM.

In conclusion, this study provides the first evidence that one of lnc-FANCI-2 functions is to maintain epithelial functional integrity by repressing RAS signaling in preventing malignant transformation of neoplastic cervical lesions. In addition, more extensive studies are underway to elucidate the role of lnc-FANCI-2 in regulation of IFN responses, which are not covered in this report. Since transactivation of lnc-FANCI-2 expression is largely dependent on host transcription factor YY1, of which expression is regulated by HPV oncoproteins and host miR-29a, dissecting their transcription network on lnc-FANCI-2 and its effectors may further provide novel insights involved in host homeostasis against HPV infection-induced carcinogenesis. Our observations also highlight additional, unexpected players beyond viral E6 and E7 that drive cells toward malignant transformation.

RNA Sequencing data have been deposited in GEO under accession code GSE190904.

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Author details

1. Haibin Liu

   Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, CCR/NCI/NIH, Frederick, United States

   Present address

   Center for Emerging Infectious Diseases, Wuhan Institute of Virology, and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Lulu Yu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3601-6066

2. Lulu Yu

   Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, CCR/NCI/NIH, Frederick, United States

   Contribution

   Data curation, Formal analysis, Validation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Haibin Liu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0309-9520

3. Vladimir Majerciak

   Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, CCR/NCI/NIH, Frederick, United States

   Contribution

   Conceptualization, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

4. Thomas J Meyer

   Collaborative Bioinformatics Resource, CCR/NCI/NIH, Bethesda, United States

   Contribution

   Software, Visualization, Methodology

   Competing interests

   No competing interests declared

5. Ming Yi

   NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, United States

   Contribution

   Software, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

6. Peter F Johnson

   Mouse Cancer Genetics Program, CCR/NCI/NIH, Frederick, United States

   Contribution

   Conceptualization, Methodology

   Competing interests

   No competing interests declared

7. Maggie Cam

   Collaborative Bioinformatics Resource, CCR/NCI/NIH, Bethesda, United States

   Contribution

   Software, Formal analysis

   Competing interests

   No competing interests declared

8. Douglas R Lowy

   Laboratory of Cellular Oncology, CCR/NCI/NIH, Bethesda, United States

   Contribution

   Supervision, Writing – review and editing

   Competing interests

   No competing interests declared

9. Zhi-Ming Zheng

   Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, CCR/NCI/NIH, Frederick, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   zhengt@exchange.nih.gov

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5547-7912

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