Table 2.
Expression and activity of key HPV-related transcription factors in normal and tumor tissues of H&N region.
| Transcription factor (family members) | Specimen | Transcription factor Activation status | Expression level of transcription factor family members | HPV-specific information | References |
|---|---|---|---|---|---|
|
AP-1 [c-Jun (39 kDa), JunB (36 kDa), JunD (35 kDa) c-Fos (41 kDa), FosB (36 kDa), Fra-1 (29 kDa), Fra-2 (35 kDa)] |
HNSCC tumors (n = 7) and adjacent control tissues | Increased binding of AP-1 in HIV LTR | Nil | Nil | (Zoumpourlis et al., 1994) |
| HNSCC cell lines UM-SCC-1, -9, -11A, -11B, and-38 | Active AP-1 with c-Jun, JunB, JunD and Fra-1 as major participants; Loss of AP-1 site reduced IL-8 promoter activity |
Nil | Nil | (Ondrey et al., 1999) | |
| HNSCC cell lines UM-SCC-9 and -11B | IL-1α-induced activation of AP-1; Loss of AP-1 site moderately reduced IL-8 promoter activity |
Nil | Nil | (Wolf et al., 2001) | |
| HPV16 E7 transgenic mouse model with dominant negative c-Jun under human K14 promoter | c-Jun associated AP-1 activation lost; Prevention of chemical-induced skin papillomas |
NIL | Increased HPV16 E7 expression in DN-c-Jun mice; more papillomas | (Young et al., 2002) | |
| HNSCC cell lines UM-SCC-9 and -11B | EGFR promoted AP-1 activity and downstream expression of VEGF | Nil | Nil | (Bancroft et al., 2002) | |
| HPV immortalized human oral keratinocytes- HOK-16B; | Acetaldehyde activates AP-1 containing c-Jun | Increased c-jun mRNA and protein accumulation | HPV-transformed cells | (Timmons et al., 2002) | |
| HNSCC cell lines: UM-SCC 1, 5, 6, 9,11A, 11B, 22A, 22B, 38, and 46 | Heterogeneity in cell lines with respect to AP-1 regulated gene expression | Nil | Nil, (Cell lines differed in their p53 expression | (Yan et al., 2007) | |
| FFPE-tissues of oral leukoplakias, with different degrees of epithelial dysplasia, and OSCC (n = 50); (HPV positivity-24%) | According to degree of oral dysplasia withing lesion c-Jun nuclear expression increased and greatest expression and nuclear localization in OSCC | Increased expression of c-Jun with increasing severity of the lesion | Malignant progression mediated by c-Jun is independent of the presence of HPV in oral carcinogenesis | (Acay et al., 2008) | |
| Fresh oral tissue specimens (n = 100) | Increased activation of AP-1 with increasing disease severity | Presence of JunD with c-Fos in AP-1 complex in majority of oral cancer; JunB showed sporadic increase in a subgroup | Nil | (Mishra et al., 2010) | |
| HPV immortalized human oral keratinocytes- HOK-16B HNSCC cell line- UM-SCC-9, 11A, 11B, 38 |
Tobacco-carcinogen induced AP-1 reporter gene activity; AP-1 activity dependent on c-Fos expression |
c-Fos expression induced by tobacco carcinogens | IL-8 and VEGF expressed both in HPV-transformed oral keratinocytes and HNSCC cell lines | (Swenson et al., 2011) | |
| Fresh tongue tissue biopsies (n-100), (HPV positivity-28%) Tongue cancer cell lines-HPV16 positive- UPCI:SCC090; HPV negative- AW13516 |
Increased activation of AP-1 with increasing disease severity; Upregulation of downstream target genes: cyclin D1, c-myc, Bcl-xl, MMP-9, EGFR Composition: c-Jun, c-Fos, Fra-2 in HPV-negative and JunD, JunB, c-Fos and Fra-2 in HPV-positive tumors |
Higher expression of all Jun and Fos family members except Fra-1 which showed reciprocal kinetics | Selective participation of JunD and JunB only in HPV16 positive tumors and cell lines; absence of c-Jun in HPV-positive | (Gupta et al., 2015) | |
| HNSCC cell line: HPV-positive- 93VU-147T | Inhibition of AP-1 activation and change in active AP-1 by curcumin | Curcumin induced loss of AP-1 c-Jun, JunD and JunB in HPV-positive oral cancer cells | Nil | (Mishra et al., 2015) | |
| HNSCC cell lines – 26; Mouse model of metastasis | Nil | JunB, Fos, Fra-1, JunD overexpressed in cells with metastatic potential | Nil | (Hyakusoku et al., 2016) | |
| Prospectively collected fresh biopsies - 116 and FFPE -30 from OSCC/OPSCC; Total tissue analyzed (n = 116), FFPE (n = 66) |
Nil | Overexpression of JunD, and c-Fos in SCC as compared to normal; Overexpression of JunB only in HPV-positive tissues | Differential increase in JunB in HPV-positive; Level of JunD upregulated but not differentially active only HPV-positive cancers |
(Verma et al., 2017) | |
| Human OSCC samples (n = 123) | Elevated expression of active AP-1 component phospho-c-Jun in resistant tumors; Active AP-1 strongly correlated with bcl-2 overexpression | c-Jun overexpression in chemo-radioresistant tumors | Nil | (Alam et al., 2017) | |
| HNSCC cell lines: HPV-negative- CAL33Res; HPV-positive- UM-SCC-47 | Overexpression of c-Jun target gene AXL | Silencing of c-JUN and c-FOS expression downregulated AXL expression and enhanced the sensitivity of HPV negative cells | Targeting AP-1 enhanced the antitumor efficacy of BYL719 against HPV positive HNSCC | (Badarni et al., 2019) | |
|
NF-κB [NF-κB1 (50 kDa), NF-κB2 (52 kDa) RelA (65 kDa), RelB (70 kDa) c-Rel (78 kDa)] |
HNSCC cell line: UM-SCC-9, -11B, and -38 | Constitutive and inducible NF-κB, and promoter activity | Overexpression of p65 in cell lines | Nil | (Duffey et al., 1999) |
| Human HNSCC cell lines: UM-SCC-1, 9, 11A, 11B, 38 | Constitutive DNA binding & promoter activity; Constituents p65/Rel A and p50; IL-8 induction: stronger role than AP-1 | Nil | Nil | (Ondrey et al., 1999) | |
| Laryngeal SCC: Tumor and non-tumor laryngeal tissues | Nuclear positivity of p65 | High levels of p65 in cytoplasm, moderate in nucleus | Nuclear p65 correlated with HPV16 E7 level | (Du et al., 2003) | |
| Oral tissue biopsies (n = 110). OSCC (n = 66) OPMD (n = 34), normal (n = 10); HPV positivity = 22%, HR-HPV16 = 18% |
Constitutively active NF-κB; increased with disease severity; Major participants:p50, p65, p52, c-Rel, RelB, and Bcl-3 | Upregulation of p50, p65 and c-Rel with increasing severity of lesion; immunoreactivity for p52, c-Rel and RelB in cancer tissues. | p50/p50 homodimerization common; Involvement of p65 only in NF-κB complex of HPV16-positive | (Mishra et al., 2006) | |
| HNSCC (n = 195); Control (n = 63; non cancer affected patients); Human HNSCC cell lines: Ho1N1, HSC2,and SKN3 | SiRNA mediated downregulation of NF-κB activity; NF-κB nuclear staining: 55.6% HPV-negatives (above median-12.85), HPV-positive below median | Overexpression of RELA, NF-κB1 | Differential gene signatures. Strong NF-κB activation in HPV-negative HNSCC |
(Gaykalova et al., 2015) | |
| OC and OPSCC Tissue biopsies (Fresh, n = 116; and FFPE, n = 66) |
Nil | Variable presence of p50 and p65 in HPV+ and HPV- tissues | p50: equal distribution among HPV-positive and HPV-negative tumors, p65: strong correlation with HPV-postive tumors |
(Verma et al., 2017) | |
| Tongue tissue biopsies (n = 100) TSCC cell line: UPCI:SCC090 and AW13516 |
Increase d activity with severity of disease; p50 and c-Rel forming NF-κB | Differential expression of NF-κB proteins | Selective participation of p65 in NF-κB complex of HPV16-positive HNSCC | (Gupta et al., 2018) | |
| STAT3 (88 kDa) | HNSCC Cell line:YCU-N861, YCU-H891; HNSCC tissues (n = 6) | Constitutive activation of EGFR and STAT3; STAT3DN66 and STAT3DN99 abrogate STAT3 activity |
Constitutive expression of STAT3 | Nil | (Masuda et al., 2002) |
| HNSCC tissues (n = 90) | High level of pSTAT3 in early stages (T1, T2), moderate in late stages (T3, T4); No STAT3 in normal samples | HNSCC - 82% with high or intermediate STAT3; No STAT3 in normal tssues | Nil | (Nagpal et al., 2002) | |
| HNSCC cell lines: HN6, HN12, HN13, HN30, HaCaT, HEK293T, HEK293FT cells; HNSCC FFPE tissues (n = 460) | pSTAT3 induction by IL-6 produced through active NF-κB signalling | STAT3 expression unaffected | Nil | (Squarize et al., 2006) | |
| HNSCC (n = 195); Control (n = 63; non cancer affected patients); Human HNSCC cell lines: Ho1N1, HSC2,and SKN3 | Transcript profiling of STAT3 with NF-κB pathway signature target genes (IRF1, CEBPD, CCND1, ICAM1, JAG1, JAK3, and NOS3); reporter gene expression | Indirect evidence | Specific signature for HPV positive and negative; 49 HPV negative, while 1 HPV positive patients stained for nuclear STAT3 above median | (Gaykalova et al., 2015) | |
| OC and OPSCC Tissue biopsies (Fresh, n = 116; and FFPE, n = 66) |
pSTAT3Y expression | Immunoblotting and Immunohistochemistry: inverse correlation between HPV positivity and STAT3/pSTAT3 expression. | HPV positive: low STAT3/pSTAT3; HPV negative: high STAT3/pSTAT3 | (Verma et al., 2017) | |
|
SOX2 (34 kDa) |
OSCC frozen tumor tissue samples (n = 40) | SOX2 overexpression associated with increased activity | High expression of SOX2 and CyclinE1 in OSCC specimens | Nil | (Freier et al., 2010) |
| HNSCC tumor tissues (n = 496) | – | SOX2 induced BCL-2 and enhanced chemo-resistance | SOX2 amplification in HPV-negative, but no amplification in HPV-positive | (Schrock et al., 2014) | |
| H&N tissue retrospectively collected (n = 94) | Nuclear positivity of SOX2 | SOX2 expression detected in 95% of laryngeal dysplasia | Nil | (Granda-Diaz et al., 2019) | |
| OPSCC (n = 157) | Nil | SOX2 overexpression with poor prognosis | Poorer overall survival in SOX2-amplified HPV-negative cases (p = 0.036) | (Dogan et al., 2019) | |
| Tongue SCC cell line- CAL‐27 | – | EGFR mediated stabilization and upregulation of SOX2 expression | Nil | (Lv et al., 2020) | |
| YY1 (44 kDa) | Laryngeal SCC Cell line - Hep-2; Control- HEK293T | Proliferation and migration with suppression of apoptosis as indicators of increased YY1 activity | YY1 upregulated in LSCC | Nil | (Qu et al., 2017) |
| NPC cases (n = 40); Stage I replication (297 cases and 611 controls); Stage II replication (768 cases and 1526 controls) | YY1-mediated repression of TRIM26 | Nil | Nil | (Lyu et al., 2018) | |
| OSCC tumor tissues (n-30); Cell lines- HEK293T, AW8507 | YY1 mediated reporter gene activation by CARM1 mediated arginine methylation | YY1 overexpressed in oral cancer | Nil | (Behera et al., 2019) | |
| SP1 (80.6 kDa) | Normal oral mucosa (n-8), OSCC (n-10); OSCC cell lines: SCC-15, YD-15 | SP-1 inhibitor downregulated expression of SP-1 and decrease tumor growth | SP-1 was overexpressed in oral tumors compared to normal | Nil | (Shin et al., 2013) |
| NPC tumors (n-82), Metastatic malignant tumors (n-60), Nonmetastatic malignant tumors (n-22) | miR-24 overexpression lead to reduced SP1 activity and inhibited proliferation | Reduced SP1 expression contributed to the reduction in radio-resistance | Nil | (Kang et al., 2016) | |
| OSCC patients (n-55); Cell line- CAL-27 and SCC9 |
Upregulated SP-1 in OSCC | SP-1 is overexpressed in OSCC and could promote cell invasion and migration in OSCC | Nil | (Liu et al., 2019) | |
| OCT-1 (76.4 kDa) | HNSCC cell line: PCI-04A | – | Ionizing radiation induce OCT-1 | Nil | (Meighan-Mantha et al., 1999) |
|
c/EBPβ (76.4kDa) |
HNSCC cell lines: UM-SCC-1, -9, -11A, -11B, and -38 | Constitutive activation | – | Nil | (Ondrey et al., 1999) |
| NPC and non-cancerous NPE (n-33); Cell line- HNE1 and 5–8F | Nil | (Wang et al., 2016) | |||
| FOXA1 (49.1 kDa)/FOXA2 (48.3 kDa) | HNSCC (n = 152) | Nil | FOXA1 expressed in basal cells of squamous epithelium, pre-invasive HNSCC lesions | Due to specificity of FOXA-1 positive site, it may have implication in HPV-mediated pathogenesis | (Karpathiou et al., 2017) |
| NPC tissues (n-114), Non-cancer inflammatory NPE tissues (n-64) | FOXA1 regulated TGF-β-stimulated transcriptome | FOXA1 protein was decreased in NPC cells; loss of FOXA1 associated with lymph node metastasis and poor prognosis. | Nil | (Li et al., 2019) |
AP-1, Activator Protein; DMBA, 7,12-dimethylbenz[a]anthracene; DN, Dominant Negative; EGFR, Epidermal Growth Factor Receptor; FFPE, Formalin-Fixed and Paraffin-Embedded; FOXA1, Forkhead Box A1; FOXA2, Forkhead Box A2; HPV, Human Papillomavirus; HNSCC, Head and Neck Squamous Cell Carcinoma; LSCC, Laryngeal Squamous Cell Carcinoma; NF-κB, Nuclear Factor-κB; NPC, Nasopharyngeal Carcinoma; NPE, Nasopharyngeal Epithelial; STAT3, Signal Transducer and Activator of Transcription – 3; SOX2, sex determining region Y (SRY)-box; SP1, Specificity Protein 1; TSCC, Tongue Squamous Cell Carcinoma; TPA, 12-O-tetradecanoylphorbol-13-acetate; OCT-1, Octamer Transcription Factor-1; OC- Oral Cancer; OSCC, Oral squamous Cell Carcinoma; OPSCC, Oropharyngeal Squamous Cell Carcinoma; OPMD, oral premalignant disease; VEGF, Vascular Endothelial Growth Factor; YY1, Yin Yang 1.