Understanding the Molecular Genetics of Basal Cell Carcinoma

Pellegrini, Cristina; Maturo, Maria Giovanna; Nardo, Lucia Di; Ciciarelli, Valeria; García-Rodrigo, Carlota Gutiérrez; Fargnoli, Maria Concetta

doi:10.3390/ijms18112485

Cited by 182 publications

(221 citation statements)

References 115 publications

(205 reference statements)

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“…Our previous finding that PTPN14 is targeted for degradation by high-risk HPV E7 but not by low-risk HPV E7 suggested that PTPN14 loss might be related to the biology of the high-risk HPV (47). PTPN14 is a candidate tumor suppressor based on the observation that it is mutated in some cancers (54,57,(78)(79)(80)(81). The targeted degradation of PTPN14 by high-risk HPV E7 requires the E3 ubiquitin ligase UBR4 and the interaction of UBR4 with papillomavirus E7 is required for E7 to transform cells (45,46).…”

Section: Discussionmentioning

confidence: 99%

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

Hatterschide

Bohidar

Grace

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV + but not HPV − cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.H uman papillomaviruses (HPVs) are nonenveloped, doublestranded DNA viruses that infect and replicate in the stratified squamous epithelium. HPV initially infects keratinocytes in the basal, proliferative layer of the epithelium, and subsequent steps in the HPV replicative cycle-including viral genome amplification, encapsidation, and egress-are dependent on keratinocyte differentiation (1-3). However, HPV genome amplification also requires components of the cellular machinery for DNA replication that are not expressed in differentiating cells. Thus, productive HPV infection must uncouple proliferation and differentiation in the epithelium. Infection with one of the 13-15 "high-risk" HPVs causes nearly all cervical cancer, some other anogenital cancer, and an increasing proportion of HPV + head and neck squamous cell carcinomas (HNSCC) (4-6). In total, HPV infection causes ∼5% of cancers worldwide.The high-risk HPV E7 oncoprotein is able to immortalize human keratinocytes and the efficiency of immortalization is increased by high-risk HPV E6 (7-9). A well-characterized activity of many HPV E7 is to bind and inactivate the retinoblastoma tumor suppressor (RB1) via the LxCxE motif present in HPV E7 conserved region 2 (10-12). In addition, HPV16 E7 can direct the proteasome-mediated degradation of RB1 (13-16). RB1 inactivation releases the inhibition of E2F transcription factors (TF), thus allowing cell cycle progression and acting as a major driver of proliferation. HPV E7 also promotes proliferation by inhibiting the CDK inhibitors p21 WAF1/CIP1 and p27 . In addition to promoting proliferation, transcriptional studies indicate that human cells harboring high-risk HPV genomes express lower levels of differentiation marker genes and that...

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Section: Discussionmentioning

confidence: 99%

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

Hatterschide

Bohidar

Grace

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Basal cell carcinoma (BCC) is the most common cancer in humans [1]. Although in most cases it does not metastasize, BCC is a significant health issue because it usually appears in exposed skin, and it must be surgically removed to avoid expansion and disfiguration.…”

Section: Introductionmentioning

confidence: 99%

TBX1 and Basal Cell Carcinoma: Expression and Interactions with Gli2 and Dvl2 Signaling

Caprio

Varricchio

Bilio

et al. 2020

IJMS

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Early events of basal cell carcinoma (BCC) tumorigenesis are triggered by inappropriate activation of SHH signaling, via the loss of Patched1 (Ptch1) or by activating mutations of Smoothened (Smo). TBX1 is a key regulator of pharyngeal development, mainly through expression in multipotent progenitor cells of the cardiopharyngeal lineage. This transcription factor is connected to several major signaling systems, such as FGF, WNT, and SHH, and it has been linked to cell proliferation and to the regulation of cell shape and cell dynamics. Here, we show that TBX1 was expressed in all of the 51 BCC samples that we have tested, while in healthy human skin it was only expressed in the hair follicle. Signal intensity and distribution was heterogeneous among tumor samples. Experiments performed on a cellular model of mouse BCC showed that Tbx1 is downstream to GLI2, a factor in the SHH signaling, and that, in turn, it regulates the expression of Dvl2, which encodes an adaptor protein that is necessary for the transduction of WNT signaling. Consistently, Tbx1 depletion in the cellular model significantly reduced cell migration. These results suggest that TBX1 is part of a core transcription network that promotes BCC tumorigenesis.

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“…The tumor originates from stem cells within hair follicles or the interfollicular epidermis and infundibulum 4,5 . Basal cell carcinoma rarely metastasizes; however, due to sheer number of people affected, the disease poses a considerable health hazard as it causes extensive morbidity through local invasion and tissue destruction 6 . The most common genetic alterations in BCC involve the Hedgehog signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Coding and noncoding somatic mutations in basal cell carcinoma

Maturo

Rachakonda

Heidenreich

et al. 2019

Preprint

Self Cite

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Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of the PTCH1 and TP53 genes and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcriptions levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 59% and TP53 in 31% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59% and 38% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. TERT promoter mutations but not THOR methylation associated with an increased expression of the reverse transcriptase subunit.Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter. Introduction,

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Understanding the Molecular Genetics of Basal Cell Carcinoma

Cited by 182 publications

References 115 publications

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

TBX1 and Basal Cell Carcinoma: Expression and Interactions with Gli2 and Dvl2 Signaling

Coding and noncoding somatic mutations in basal cell carcinoma

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