BACKGROUND: Oral cancers have limited diagnostic tools to aid clinical management. Current evidence indicates that alterations in hemidesmosomes, the adhesion complexes primarily involved in epithelial attachment to the basement membrane, are correlated to cancer phenotype for multiple cancers. This systematic review aimed to assess the experimental evidence for hemidesmosomal alterations, specifically in relation to oral potentially malignant disorders and oral squamous cell carcinomas.
METHODS: We conducted a systemic review to summarise the available literature on hemidesmosomal components and their role in oral pre-cancer and cancer. Relevant studies were retrieved from a comprehensive search of Scopus, Ovid MEDLINE, Ovid Embase and Web of Science.
RESULTS: 26 articles met the inclusion criteria, of which 19 were in vitro studies, 4 in vivo studies, 1 in vitro and in vivo study, and 2 in vitro and cohort studies. Among them, 15 studies discussed individual alpha-6 and/or beta-4 subunits, 12 studies discussed the alpha-6 beta-4 heterodimers, 6 studies discussed the entire hemidesmosome complex, 5 studies discussed bullous pemphigoid-180, 3 studies discussed plectin, 3 studies discussed bullous pemphigoid antigen-1 and 1 study discussed tetraspanin.
CONCLUSIONS: Heterogeneity in cell type, experimental models, and methods were observed. Alterations in hemidesmosomal components were shown to contribute to oral pre-cancer and cancer. We conclude that there is sufficient evidence for hemidesmosomes and their components to be potential biomarkers for evaluating oral carcinogenesis.

Collagen type XVII α1 (COL17A1) encodes a hemidesmosomal protein at the epidermal-dermal junction and its variants are implicated in blistering skin diseases. Recent experiments in rodents revealed that Col17a1 has critical roles in stem cells of epidermal origin and in melanoma carcinogenesis. In the present study, it was investigated whether germline variants in COL17A1 are associated with skin cancer and other cancer types using indexed consecutive autopsy cases from the Japanese Geriatric Single Nucleotide Polymorphism database (n=2,343; mean age, 80 years). The database included 12 patients with skin cancer. A total of 53 COL17A1 missense variants on an exome chip were analyzed. One variant, p.Ser1029Ala (rs118166857), which had a minor allele frequency of 1.0%, exhibited a nominal positive sign of association with skin cancer [Fisher\'s exact P=0.002, odds ratio (OR)=16.93, 95% CI: 4.44-64.64]. This variant was detected in 2/2 patients with mucosal malignant melanoma (mMM) and 1/3 patients with extramammary Paget\'s disease, and in none of the patients with non-melanoma cancer, e.g., squamous cell and basal cell carcinoma. Other cancer types were searched in the database and the p.Ser1029Ala variant was indicated to be nominally associated with breast cancer (P=0.006, OR=4.17, 95% CI: 1.72-10.11). In the two mMM cases, targeted exome sequencing of 55 cancer-predisposing genes (including tumor protein 53, BRCA1/2 and mismatch repair genes) detected no apparent pathogenic variants, but revealed variants of unknown significance in axin 2, DNA directed polymerase ζ catalytic subunit and contactin 6. Since COL17A1 provides a niche for melanocyte stem cells, it was hypothesized that the p.Ser1029Ala variant in the COL17A1 ectodomain may affect the microenvironment, e.g., the cell competition. This is a working hypothesis generated from human autopsy cases and warrants further epidemiological and molecular biological validation.

Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes.

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is induced by autoantibodies to type XVII collagen (COL17). Previous studies demonstrated that COL17 harbors several epitopes targeted by autoreactive T and B cells and that the target epitopes change sequentially during the disease course. To elucidate the details of the humoral immune response to COL17, we used an active BP mouse model in which BP is induced by the adoptive transfer of spleen cells from wild-type mice immunized with human COL17-expressing skin grafting to immunodeficient COL17-humanized (Rag-2-/-, mouse Col17-/-, human COL17+) mice. By immunoblot analysis, antibodies to the NC16A domain and other extracellular domains (ECDs) of COL17 were detected earlier than antibodies to intracellular domains (ICDs) in the active BP model. Time course analysis by enzyme-linked immunosorbent assay demonstrated a delayed peak of antibodies to ICD epitopes in active BP model. The blockade of CD40-CD40 ligand interaction soon after the adoptive transfer suppressed the production of antibodies to the non-collagenous 16A (NC16A) domain but not to an ICD epitope, suggesting the sequential activation from T and B cells against the ECD epitopes including the NC16A domain to those against ICD epitopes in vivo. Both wild-type mice immunized with a fragment of the NC16A domain and the recipients of those spleen cells produced IgG antibodies to ICD and ECD epitopes, showing intramolecular epitope spreading from the NC16A domain to other epitopes of COL17. Furthermore, we found that a portion of the active BP model mice show intermolecular epitope spreading from human COL17 to murine BP230. The appearance of antibodies to ICD epitopes of COL17 or of antibodies to murine BP230 did not correlate with the skin changes in the mice, suggesting that those antibodies have low pathogenicity. These results suggest that the immune response to the ECD epitopes of COL17, especially to the NC16A domain, triggers intramolecular, and intermolecular epitope spreading to ICD epitopes of COL17 and to murine BP230. These novel findings provide insight into the mechanism of epitope spreading in organ-specific, antibody-mediated autoimmune disorders.