Promoter mutations/methylation in thyroid and urothelial carcinomas : biological and clinical implications
Genetic and epigenetic aberrations are well established to drive cancer development and progression. However, the underlying mechanisms are incompletely understood, and the translational applications of aberrant alterations are limited in gene non-coding regions, such as the promoter locus. The present thesis aims to address the relevant molecular basis to contribute further insights of how genetic/epigenetic events involved in oncogenesis of thyroid cancer (TC) and upper tract urothelial carcinoma (UTUC).
In Paper I, we characterized Pleckstrin homology domain-containing family S member 1 (PLEKHS1) promoter mutation/methylation, gene expression and its role in TCs including papillary and anaplastic thyroid carcinomas (PTCs and ATCs). The PLEKHS1 promoter mutation was rare in TC, but PLEKHS1 was significantly over-expressed in TCs compared to adjacent thyroid tissues. ATC tumors, the most aggressive TC subtype, expressed the highest level of PLEKHS1. Mechanistically, the demethylation of the PLEKHS1 promoter contributes to its over-expression in TC tumors. We further revealed that higher PLEKHS1 expression led to increased AKT phosphorylation and invasive phenotype of TC cells. Consistently, PLEKHS1 over-expression was associated with TC metastasis, and predicted shorter patient survival. Taken together, it is the hypomethylation of PLEKHS1 promoter rather than its mutation that induces PLEKHS1 over-expression, thereby enhancing AKT activity and aggressive behavior of TC cells. Clinically, PLEKHS1 may be a useful prognostic factor in PTCs.
In Paper II, the role for GABPB1 in TC pathogenesis was investigated. It has been characterized that GABPB1 and its partner GABPA stimulates the mutated telomerase reverse transcriptase (TERT) promoter for telomerase activation in TCs or other cancers. Targeting GABPB1 is thus suggested as a strategy for telomerase-based cancer therapy. However, GABPB1 depletion promoted TC cell invasion, although TERT expression was reduced in those cells. We further observed that GABPB1 expression was significantly lower in aggressive TCs, potentially attributed to its promoter hypermethylation. Collectively, GABPB1 may function as a tumor suppressor to impede TC aggressiveness, whereas the GABPB1 silencing via the aberrant DNA methylation is required to facilitate TC progression. Therefore, targeting GABPB1 for TC therapy might promote disease dissemination rather than cure patients.
In Paper III, we analyzed TERT and PLEKHS1 promoter mutations in urothelial carcinomas [UTUC and urothelial bladder carcinoma (UBC)] and evaluate whether they could serve as urinary biomarkers for disease diagnosis and monitoring. In addition, the mutation of the G protein-coupled receptor 126 (GPR126) intron 6 was recently observed in UBC, and we included this marker in the study. By using Sanger sequencing, we identified that the frequencies of TERT, PLEKHS1 and GPR126 gene mutations occurred in UTUCs but with lower frequencies compared to UBCs. The mutant DNA sequences were readily detected in patients’ urine and disappeared in most patients after surgical treatment. Thus, the mutations in the TERT, PLEKHS1 and GPR126 regulatory regions occur in UTUCs, and they may serve as urinary biomarkers for UTUC diagnostics and surveillance.
In summary, the present thesis demonstrated how mutations or aberrant DNA methylation of TERT, GABPB1, PLEKHS1 and GPR126 genes occur in TC and UTUC, and how these events interact together or function independently to participate in TC and UTUC pathogenesis. Our findings are of potential importance in improving the management of these patients.
List of scientific papers
I. Xiangling Xing, Ninni Mu, Xiaotian Yuan, Na Wang, C. Christofer Juhlin, Klas Strååt, Catharina Larsson, Dawei Xu. PLEKHS1 over-expression is associated with metastases and poor outcomes in Papillary Thyroid Carcinoma. Cancers. 2020, 12(8), 2133.
https://doi.org/10.3390/cancers12082133
II. Xiaotian Yuan, Ninni Mu, Xiangling Xing, Na Wang, C. Christofer Juhlin, Klas Strååt, Catharina Larsson, Dawei Xu. Downregulation and hypermethylation of GABPB1 is associated with aggressive thyroid cancer features. [Manuscript]
III. Xiangling Xing, Xiaotian Yuan, Tiantian Liu, Mingkai Dai, Yidong Fan, Cheng Liu, Klas Strååt, Magnus Björkholm, Dawei Xu. Regulatory region mutations of TERT, PLEKHS1 and GPR126 genes as urinary biomarkers in upper tract urothelial carcinomas. Journal of Cancer. 2021; 12(13): 3853-3861.
https://doi.org/10.7150/jca.56779
History
Defence date
2021-10-29Department
- Department of Medicine, Solna
Publisher/Institution
Karolinska InstitutetMain supervisor
Xu, DaweiCo-supervisors
Björkholm, Magnus; Strååt, Klas; Yuan, XiaotianPublication year
2021Thesis type
- Doctoral thesis
ISBN
978-91-8016-326-2Number of supporting papers
3Language
- eng