PTTG: an important target gene for ovarian cancer therapy

Abstract

Pituitary tumor transforming gene (PTTG), also known as securin is an important gene involved in many biological functions including inhibition of sister chromatid separation, DNA repair, organ development, and expression and secretion of angiogenic and metastatic factors. Proliferating cancer cells and most tumors express high levels of PTTG. Overexpression of PTTG in vitro induces cellular transformation and development of tumors in nude mice. The PTTG expression levels have been correlated with tumor progression, invasion, and metastasis. Recent studies show that down regulation of PTTG in tumor cell lines and tumors in vivo results in suppression of tumor growth, suggesting its important role in tumorigenesis. In this review, we focus on PTTG structure, sub-cellular distribution, cellular functions, and role in tumor progression with suggestions on possible exploration of this gene for cancer therapy.

Figure 1

The cluster analysis of three human PTTG homolog cDNA sequences. The sequences were analyzed by ANTHEPROT 2000 V6.0. PTTG1, PTTG2 and PTTG3 are the human PTTG isoforms 1, 2 and 3 respectively. The conserved sequences across all these isoforms are shown in row 4. The nucleotide identity is shown in different colors. Red indicates 100% identity, Blue ≥ 75, dark green ≥ 50 and light green < 50.

Figure 2

The Neighbor phylogenetic tree analysis of human PTTG homologues. PTTG1, PTTG2 and PTTG3 are the human PTTG isoforms 1, 2 and 3 respectively.

Figure 3

The cluster analysis of PTTG cDNA sequences from different species. The sequences were analyzed by ANTHEPROT 2000 V6.0. PTTG cDNA sequences of human, chimpanzee, gorilla, cow, mouse and rat were analyzed in rows 1, 2, 3, 4, 5, and 6 respectively. The conserved sequences across all these species are shown in row 7. The nucleotide identity is shown in different colors. Red indicates 100% identity, Blue ≥ 75, dark green ≥ 50 and light green < 50.

Figure 4

The Neighbor phylogenetic tree analysis of PTTG from different species. PTTG cDNA sequences of human, chimpanzee, gorilla, cow, mouse and rat were analyzed in rows 1, 2, 3, 4, 5, and 6 respectively.

Figure 5

The northern blotting analysis of PTTG expression in various ovarian cancer patients. N indicates normal ovarian tissue and T indicates the ovarian cancer tissue from the corresponding patient. The numeric 1, 2, 3, and so on indicates the tissues different patients.

Figure 6

Histopathological analysis of the ovaries from transgenic and non-transgenic animals. Transgenic animals showed enlarged ovaries, and presence of large number of corpus lutea compared to non-transgenic animals. The size of the ovaries in μm² from transgenic and non-transgenic animals was determined by measuring the length and width of histological sections at 4× magnification using Metmorph Software version 6.2. The figure was reproduced with permission from J Endocrinology (6).

Figure 7

Histological analysis of PTTG transgenic uterus. The uteri from transgenic mice (a and b) had large cysts and multiple small fluid-filled glandular cysts compared to non transgenic mice (e and f). Scar formation and hemosiderin laden granules (asterisk in f) were evident in wild-type but absent in transgenic uterus. Both wild-type and transgenic uteri were PCNA positive; PCNA staining in transgenic uteri of transgenic animals was much darker and homogeneous compared to non-transgenic animals, suggesting the presence of highly proliferative cells both in luminal and glandular epithelium. Negative control sections in which primary antibody were omitted did not display any PCNA staining (h). The figure was reproduced with permission from J Endocrinology [6].

Figure 8

LH and testosterone levels in transgenic and wild-type animals. Serum concentration of LH (A) and testosterone (B) were measured in 8- to 10-month old transgenic and wild-type females using EIA kit. The data was reproduced with permission from J Endocrinology [6].

Figure 9

Regulation of PTTG expression by various growth factors and predicted biological and tumorigenic functions. The regulatory factors and pathways regulated by PTTG are shown.