CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer

Abstract

The CHL1 gene encodes a cell-adhesion molecule proposed as being a putative tumour-suppressor gene in breast cancer (BC). However, neither the underlying molecular mechanisms nor the clinical value of CHL1 downregulation in BC has been explored. The methylation status of three CpG sites in the CHL1 promoter was analysed by pyrosequencing in neoplastic biopsies from 142 patients with invasive BC and compared with that of non-neoplastic tissues. We found higher CHL1 methylation levels in breast tumours than in non-neoplastic tissues, either from mammoplasties or adjacent-to-tumour, which correlated with lower levels of protein expression in tumours measured by immunohistochemistry. A panel of five BC cell lines was treated with two epigenetic drugs, and restoration of CHL1 expression was observed, indicating in vitro dynamic epigenetic regulation. CHL1 was silenced by shRNA in immortalized but non-neoplastic mammary cells, and enhanced cell proliferation and migration, but not invasion, were found by real-time cell analysis. The prognostic value of CHL1 hypermethylation was assessed by the log-rank test and fitted in a Cox regression model. Importantly, CHL1 hypermethylation was very significantly associated with shorter progression-free survival in our BC patient series, independent of age and stage (p = 0.001). In conclusion, our results indicate that CHL1 is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in BC.

Close homologue of L1 sensitizes lung cancer cells to cisplatin and paclitaxel via inhibition Akt pathway

“…promote human cervical cancer cells invasion and migration through negative regulation of CHL1 (Chu et al 2014, Long et al 2012). In the majority tumors, CHL1 is a potential tumor suppressor gene, whose silencing is attribute to tumor growth, invasion and metastasis (He et al 2013, Martin-Sanchez et al 2017, Morellini et al 2007, Tang et al 2019, Zhu et al 2014).…”

“…In esophageal squamous cell carcinoma (ESCC), CHL1 down-regulation was associated with invasion, lymph-node metastasis, and poor overall survival (Tang et al 2019). The expression of CHL1 was downregulated by hypermethylation in human breast cancer, and it negative expression was contribute to breast tumorigenesis and progression (He et al 2013, Martin-Sanchez et al 2017). In thyroid cancer (Zhu et al 2014), and colonic adenocarcinoma (Yu et al 2018), CHL1…”

CHL1 expression differentiates Hürthle cell carcinoma from benign Hürthle cell nodules

“…Knockdown of CHL1 promoted the tumorigenicity of BC both in vitro and in vivo . CHL1 hypermethylation was an independent prognostic factor in patients with BC . It has also been postulated that CHL1 might have a dual role in the pathophysiology of cancer: in early preinvasive growth in ovarian, colon, and breast tumors, CHl1 could serve as a tumor suppressor gene and can be silenced; at later stages of invasion and metastasis, it may be re‐expressed on the edge of the tumor to drive local invasion and enable metastatic spread .…”

Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix

“…Two replicates for each condition were analyzed. Cell attachment, spreading and proliferation were monitored by real-time cell analysis for 7 days, on the basis of changes in cell-sensor impedance, as previously described [47]. To assess the invasive capability of CC cell lines, cells were starved overnight.…”