Telomerase activation without shortening of telomeric 3′‐overhang is a poor prognostic factor in human colorectal cancer

Abstract

Our previous report demonstrated a good correlation between high telomerase activity of cancer tissues and a poor prognosis of patients with colorectal cancers, except for several cases. To elucidate the additional factors that contribute to patient prognosis, the correlation among the expression levels of telomere binding proteins (TBP), the lengths of telomeres, the lengths of telomere 3¢-overhang (3¢-OH) and telomerase activity in 106 paired colorectal cancer and corresponding noncancerous mucosa (NCM) specimens were examined. The expression levels of eight TBP genes (TRF1, TRF2, TIN2, TANK1, TANK2, POT1, RAP1 and TPP1) were analyzed. Among the 106 cases, 35 cases had shortened telomeres (<7 kb), 15 had shortened 3¢-OH (3¢-OH length ratio of cancer/NCM <0.5) and 88 were classified as telomerase-activated cancers (activity ratio of cancer/NCM >2). Comparison between NCM and cancer in each case showed that all TBP except for POT1 were downregulated in cancers. A survival analysis using a Cox proportional hazard model showed that the survival rate of the telomerase-activated cases with shortened 3¢-OH and that of telomerase-inactivated cases were significantly better than that of telomerase-activated cases without 3¢-OH shortening, that is, restored or maintained 3¢-OH (P = 0.018). In the telomeraseactivated cancers, the length of 3¢-OH was significantly correlated with the expression levels of POT1. Elongation of telomeric overhang by telomerase, which might be regulated by POT1, may contribute to the increase of malignant potential in colorectal cancers. (Cancer Sci 2011; 102: 330-335) T he ends of chromosomes, named telomeres, are characterized by guanine-rich tandem hexamers (5¢-TTAGGG-3¢) with an average length of 5-15 kb and they serve as protective caps.(1,2) During DNA replication in cell division, telomeres gradually shorten at a rate of 50-200 bp as a result of the incomplete replication of linear chromosomes, the so-called 'end-replication problem'.(3) The telomeres terminate in a 3¢-single-stranded overhang of 12-300 bp, that is, ''telomere 3¢-overhang (3¢-OH)'' of the G-rich strand, which can be extended by telomerase in the S phase, followed by fill-in of the C strand in the late S phase.(4) Telomerase is a ribonucleoprotein that catalyzes de novo synthesis and elongation of telomeric repeats at chromosomal ends using an intrinsic RNA template in eukaryotic cells with an extended lifespan. The telomere overhang folds back into the D-loop of the duplex telomeric DNA to form a protective ''T-loop'' that prevents degradation by exonucleases or processing as damaged DNA.(5) This loop hides the 3¢ end also from telomerase. Furthermore, the telomeric repeats are bound to a large protein complex called ''shelterin'',which involves several telomere binding proteins (TBP). This complex is proposed to regulate telomere length, telomere protection and other cell functions such as proliferative activity.(5) When the telomere length shortens to a limited length, cells fall into senescence due to cleavage of ...

Telomere Length as a Prognostic Factor for Overall Survival in Colorectal Cancer Patients

“…Previous studies have suggested that the maintenance of telomere length through the reactivation of telomerase is a prerequisite for tumors to preserve their ability to proliferate and grow [8][9][10][11]. So far, there were several studies exploring the prognostic role of telomere length in colorectal cancer, but no consistent findings were reported [12][13][14][15][16]. Therefore, it is necessary to assess all data and elucidate those controversial or inconclusive results.…”

“…The number of participants with colorectal cancer ranged from 57 to 571 (Table 1). The study by Kojima et al reported that telomere length was not associated with the survival of colorectal cancer, but didn't report the exact HR with 95%CI [13]. The outcome of quality assessment was shown in the Table 1.…”

“…One publication contained three individual cohort studies, and was extracted as three different cohort studies [15]. Thus, 7 individual studies from 5 articles were included [12][13][14][15][16]. Those 7 studies included a total of 956 Table 1 (Table 1).…”

“…1). After screening the titles and abstracts, 130 articles were excluded and 6 publications were further assessed by reviewing full-texts [12][13][14][15][16]21]. After full-text review, one publication was excluded for containing overlapping data [21].…”

The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis

“…Studies have also found that telomerase can induce cell expression of epidermal growth factor (EGFR) (39) or transforming growth factor-β (TGF-β) (40) to stimulate cell proliferation. In fact, prognostic values of TA for overall survival in CRC patients are significantly correlated, those who had telomerase activated without 3'OH shortened telomeres had a poor prognosis (41). Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors (19).…”