Telomerase reverse transcriptase (TERT) : promoter mutation and novel function in human cancer

Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase, an RNAdependent
DNA polymerase responsible for telomere elongation. TERT is transcriptionally repressed
in most normal human somatic cells with limited life-span, which contributes to telomerase silence. It
is well established that maintenance of telomere length is essential to cellular immortalization and
malignant transformation, and predominantly achieved through TERT induction and subsequent
telomerase activation. Evidence has also accumulated that, apart from its canonical telomerelengthening
function, telomerase or TERT exhibits many other biological activities, thereby
promoting cancer progression. Given its critical role in cancer formation and differential expression
between normal and malignant cells, TERT/telomerase has been suggested as a novel cancer
diagnostic marker and therapeutic target. To rationally develop these telomerase-based clinical
applications, it is a demanding task to gain profound insights into the regulatory mechanism
underlying cancer-specific TERT expression or telomerase activation, and to delineate various roles
of TERT/telomerase in cancer development/progression. My thesis thus focuses on these important
issues. Specifically, I sought to determine: (i) the biological role and clinical implication of the
somatic TERT promoter mutation, and (ii) the regulatory effect of TERT on the oncogenic factor
cyclooxygenase2 (COX2) in human cancer.



The somatic TERT promoter mutation, initially identified in malignant melanoma, stimulates TERT
gene transcription and activates telomerase. To see whether this genetic event occurs in the
pathogenesis of thyroid and gastric cancer, we sequenced the TERT promoter region in tumor
specimens derived from patients with premalignant thyroid lesions, thyroid and gastric cancer
(papers I, II and III). A moderate to high frequency of TERT promoter mutations was observed in
follicular cell-derived but not in parathyroid C cell-derived thyroid cancer. The mutation was
correlated with senior age, shorter telomere length, aggressive disease and shorter disease-specific
survival in thyroid cancer. Importantly, we found the mutation in a fraction (up to 17%) of
premalignant thyroid lesions, coupled with TERT and telomerase expression, which indicates that
TERT promoter mutations are early genetic events in thyroid carcinogenesis. In contrast, none of
tumors from 200 patients with gastric cancer harbored TERT promoter mutations, suggesting
different mechanisms for telomerase activation in gastric cancer.



One of non-canonical TERT functions is to serve as a transcription co-factor to regulate gene
expression. We thus determined whether the manipulating TERT expression affected the abundance
of the oncogenic factor COX2 in cancer cells (paper IV). The inhibition of TERT in cancer cell lines
using RNA interference led to a robust increase in COX2 expression at both mRNA and protein
levels through a p38 MAPK signal pathway. TERT depletion alone did not affect cell survival, while
the COX2 inhibitor together with TERT inhibition synergistically induced apoptosis of cancer cells.
TERT depletion combined with the COX2 inhibitor administration significantly inhibited tumor
growth in the mouse xenograft model of human gastric cancer. These findings reveal a novel function
of TERT and have implications in telomerase-based anti-cancer therapy.



In conclusion, the TERT promoter mutation is an early genetic event activating telomerase in the
thyroid carcinogenesis, and associated with the aggressive disease and serves as a useful prognostic
factor in thyroid cancer. The COX2 induction by TERT inhibition likely protects cancer cells from
apoptosis. Thus simultaneously targeting TERT and COX2 may have synergistic killing effects on
cancer cells, thereby improving treatment efficacy in a telomerase-based anti-cancer strategy