In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

Abstract

BackgroundMetastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis.MethodsWe systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers.ResultsIn breast cancer, various tests show that COL4A1 and COL4A2 overexpression and COL17A1 (BP180, BPAG2) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17–1.34, p = 3.03 × 10−10; HR = 1.18, 95% CI = 1.11–1.25, p = 8.11 × 10−10; HR = 0.86, 95% CI = 0.81–0.92, p = 4.57 × 10−6; respectively). Immunohistochemistry on ductal breast cancers confirmed that the COL17A1 protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown.ConclusionsParadoxically, collagen XVII is underexpressed in breast cancer and overexpressed in cervical and other epithelial cancers. However, the COL17A1 promoter methylation status accurately predicts both the direction of misexpression and the increased invasive nature for five out of five epithelial cancers. This implies that aberrant epigenetic control is a key driver of COL17A1 gene misexpression and tumor cell invasion. These findings have significant clinical implications, suggesting that the COL17A1 promoter methylation status can be used to predict patient outcome. Moreover, epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0290-6) contains supplementary material, which is available to authorized users.

The role of collagen in cancer: from bench to bedside

“…The increased expression of COLIV and COLVI and the collagen structure reflect tumor angiogenesis and glioblastoma progression [162]. Even hypomethylation of the COL17A1 promoter is associated with advanced stage, increased invasion of breast cancer, lung adenocarcinoma, cervical cancer, neck SCC, and lung SCC [163]. Factors other than collagen content are correlated with clinical outcome [164], such as collagen alignment and distribution, which also affect cancer.…”

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond

“…At the transcriptional level, overexpression of collagen XVII mRNA was found in the invasive tumors via reverse-transcriptase polymerase chain reaction (RT-PCR) at the epidermal level and within epithelial tissues. RT-PCR and northern hybridization confirmed the enhanced expression of collagen XVII in SCC (7,55). Among oral keratinocytes stimulated with the tumor promoting phorbol ester (56), a 1.5-fold induction in collagen XVII mRNA expression was noted (53).…”

“…The mechanism of tumor progression from the perspective of tumor stroma has provided a new outlook on cancer development. Following this model, studies have shown that extracellular matrix (ECM), historically considered a structural barrier to tumor cell migration, likely facilitates the first steps of cancer cell metastasis and supports tumor progression (6,7).…”

Identificação e anotação funcional de novos transcritos com expressão alterada no câncer pancreático

“…COL17A1 : codifica a cadeia alfa da proteína transmembrana colágeno XVII. No microambiente tumoral, níveis alterados de proteínas de matriz extracelular (como colágeno) podem facilitar os primeiros passos da invasão celular (metástase) em outros tecidos e sangue (Thangavelu et al 2016) . Particularmente, metilações no promotor de COL17A1 foram associadas com pior prognóstico no câncer epitelial (Thangavelu et al 2016) .…”

“…No microambiente tumoral, níveis alterados de proteínas de matriz extracelular (como colágeno) podem facilitar os primeiros passos da invasão celular (metástase) em outros tecidos e sangue (Thangavelu et al 2016) . Particularmente, metilações no promotor de COL17A1 foram associadas com pior prognóstico no câncer epitelial (Thangavelu et al 2016) . A sobre-expressão de UCA1 também foi correlacionada com resistência a quimioterápicos como gemcitabina, cisplatina, tamoxifen, 5-FU, imatinib e EGFR-TKIs, enquanto que a inativação de UCA1 restabelece a sensibilidade às drogas (H. Wang et al 2017) .…”