The molecular genetic events underlying thyroid carcinogenesis are not well understood. Mice harboring a dominant-negative mutant thyroid hormone receptor-β (TRβPV/PV mice) spontaneously develop follicular thyroid carcinoma similar to human cancer. The present study aimed to elucidate the role of the steroid receptor coactivator-3 (SRC-3) in thyroid carcinogenesis in vivo by using the offspring from the cross of TRβPV/PV and SRC-3−/− mice. TRβPV/PV mice deficient in SRC-3 (TRβPV/PVSRC-3−/− mice) had significantly increased survival, decreased thyroid tumor growth, delayed tumor progression and lower incidence of distant metastasis as compared with TRβPV/PV mice with SRC-3 (TRβPV/PVSRC-3+/+ mice). Further, in vivo and in vitro analyses of multiple signaling pathways indicated that SRC-3 deficiency could lead to (1) inhibition of cell cycle progression at the G1/S transition via controlling the expression of cell cycle regulators, such as E2F1; (2) induction of apoptosis by controlling the expression of the Bcl-2 and caspase-3 genes and (3) suppression of neovascularization and metastasis, at least in part, through modulating the vascular endothelial growth factor gene expression. Taken together, SRC-3 could play important roles through regulating multiple target genes and signaling pathways during thyroid carcinogenesis, understanding of which should direct future therapeutic options for thyroid cancer.
Thyroid cancer, the most common endocrine malignancy, has the fastest growing incidence of all cancers in the United States. Thyroid cancers in humans consist of an array of several different histological and biological types (Gillenwater and Weber, 1997), but the majority of clinically important human thyroid cancers are of the differentiated papillary and follicular types. Although the patients with differentiated thyroid cancer have a good prognosis, recurrence could develop in 20–40% of patients, and with occurrence of distance metastases and extensive local invasion, the prognosis is much poorer. The molecular mechanisms underlying the initiation and progression of thyroid carcinoma are not fully understood, but it is generally believed that deregulation of cell growth and cell death are involved.
The creation of a mouse model of follicular thyroid cancer (TRβPV/PV mice) has provided a valuable tool to understand the molecular genetic events underlying thyroid carcinogenesis. The TRβPV/PV mouse was created by a targeted mutation of thyroid hormone-β receptor (TRβPV) via homologous recombination and the Cre-LoxP system (Kaneshige et al., 2000). The thyroid hormone receptor-β mutant (denoted as PV) was identified in a patient (PV) with resistance to thyroid hormone (RTH) (Parrilla et al., 1991). RTH is caused by mutations of the TRβ gene and manifests symptoms as a result of decreased sensitivity to the thyroid hormone (T3) in target tissues (Olateju and Vanderpump, 2006). PV has a C-insertion at codon 448 that produces a frameshift in the C-terminal 14 amino acids of TRβ1. PV has completely lost T3 binding and exhibits potent dominant-negative activity (Meier et al., 1992). As TRβPV/PV mice age, they spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer with pathological progression from hyperplasia to vascular invasion, capsular invasion, anaplasia and eventually metastasis (Suzuki et al., 2002; Ying et al., 2003a, 2003b).
The steroid receptor activator-3 (SRC-3) is a member of p160 family that complexes with members of the steroid/thyroid hormone receptor superfamily to modulate their transcriptional activity (Liao et al., 2002; Lonard and O’Malley, 2005). It was initially identified as an estrogen receptor coactivator amplified in breast and ovarian cancer (Anzick et al., 1997). Subsequently, SRC-3 has been found overexpressed and/or amplified in other steroid hormone-sensitive tumors, such as prostate cancer and meningioma, as well as nonsteroid hormone-targeted tumors, such as pancreatic cancer, gastric cancer, colorectal carcinoma and hepatocellular carcinoma (Yan et al., 2006a). Transgenic mice overexpressing SRC-3 display many types of malignancy in multiple tissues, such as mammary gland, pituitary, uterus, lung, liver and skin, through activation of insulin growth factor (IGF)/AKT signaling (Torres-Arzayus et al., 2004).
Even though there have been some studies on the oncogenic functions of SRC-3 in other cancers (Liao et al., 2002), the roles of SRC-3 in thyroid carcinogenesis are not known. To ascertain its effects on thyroid carcinogenesis, we crossed TRβPV/PV mice with SRC-3 null mice (Xu et al., 2000) and evaluated thyroid tumor development and progression in the offspring. We reported previously that deficiency in SRC-3 lessened the dysfunction of the pituitary–thyroid axis, indicating its important role in the modulation of RTH (Ying et al., 2005). In the present study, we further show that deficiency in SRC-3 delayed thyroid carcinogenesis of TRβPV/PV mice by increasing survival, reducing tumor growth and increasing apoptosis. Thus, SRC-3 is a tumor promoter in thyroid carcinogenesis in a mouse model of thyroid cancer.
Deficiency of SRC-3 increases survival of TRβPV/PV mice
We have previously shown that TRβPV/PV mice have high mortality caused by follicular thyroid carcinoma. To evaluate the effect of SRC-3 on thyroid carcinogenesis, we first compared the survival curves of TRβPV/PV mice with or without ablation of the SRC-3 alleles (Figure 1a). Analysis of the data shows that the 50% survival ages for TRβPV/PVSRC-3−/− and TRβPV/PVSRC-3+/+ mice were 280±33 and 226±8 days, respectively. These data indicate that TRβPV/PVSRC-3+/+ mice died at a significantly younger age than TRβPV/PVSRC-3−/− mice did (P<0.001). When the survival curves were analysed separately for males and females (Supplemental Figure A), similar significant increases in survival of TRβPV/PV mice by SRC-3 deficiency were observed.
Deficiency of SRC-3 inhibits thyroid growth of TRβPV/PV mice
The above results prompted us to evaluate the effect of SRC-3 deficiency on thyroid growth of TRβPV/PV mice. Figure 1b compares the ratios of thyroid weight versus body weight of age-matched TRβPV/PV mice with or without SRC-3 as they aged. Consistent with our previous studies (Suzuki et al., 2002; Ying et al., 2003b; Kato et al., 2004, 2006), thyroid growth of TRβPV/PVSRC-3+/+ mice (shown as ratios) increased in an age-dependent manner (solid bars, Figure 1b). Thyroid weights of TRβPV/PVSRC-3−/− mice also increased, but clearly at reduced rates (open bars, Figure 1b). The extent of increases of thyroid weights of TRβPV/PVSRC-3−/− mice was only 49, 42, 41 and 52% of that of TRβPV/PVSRC-3+/+ mice at age 3–5, 6–8, 9–11 and 12–14 months, respectively. These results show that lack of SRC-3 significantly inhibited thyroid growth in TRβPV/PV mice as they aged. No gender differences in the inhibitory effect of thyroid growth by SRC-3 deficiency were noted (Supplemental Figure B).
Deficiency of SRC-3 delays thyroid tumor progression of TRβPV/PV mice
To understand whether lack of SRC-3 affected thyroid tumor progression, we carried out histopathological analysis and compared the percentage occurrence of capsular and vascular invasion and metastasis in TRβPV/PV mice with or without SRC-3 (Figure 2). Capsular and vascular invasion and metastasis are the main diagnostic criteria to distinguish between the benign and malignant lesions of human thyroid. While more than 90% of TRβPV/PV mice developed capsular invasion between 6 and 14 months (closed bars, Figure 2a), a significant 50% reduction in the occurrence of capsular invasion was observed in TRβPV/PV mice deficient in SRC-3 (open bars, Figure 2a). While more than 55% of TRβPV/PV mice developed vascular invasion between 6 and 14 months (closed bars, Figure 2b), no vascular invasion was detected for TRβPV/PV mice deficient in SRC-3 until the age of 12–14 months with a significant 80% reduction in the occurrence as compared to TRβPV/PVSRC-3+/+ mice (open bar, Figure 2b). Similarly, while 10, 45 and 65% of TRβPV/PVSRC-3+/+ mice developed lung metastasis at the ages of 6–8, 9–11 and 12–14 months, respectively, no metastasis occurred for TRβPV/PVSRC-3−/− mice at the age of 6–8 months. At the ages of 9–11 and 12–14 months, only 10 and 30% of TRβPV/PVSRC-3−/− mice developed metastasis. Taken together, these results indicate that ablation of two alleles of SRC-3 in TRβPV/PV mice significantly delays thyroid tumor progression.
Lack of SRC-3 inhibits thyroid growth via inhibiting cell cycle progression
SRC-3 has been reported to play an important role in cell cycle progression (Louie et al., 2004, 2006). To address the question of how SRC-3 ablation reduced thyroid growth (Figure 1b), we compared the cell cycle distribution in the thyroid tumors of TRβPV/PVSRC-3−/− mice with age-matched TRβPV/PVSRC-3+/+ mice. As shown in Figure 3a, a significant increase in the G1/G0 (compare bar 2 with 1) phase accompanied by a decrease in the G2/M phase (compare bar 6 with 5) was detected in TRβPV/PVSRC-3−/− mice as compared with TRβPV/PVSRC-3+/+ mice, indicating that the lack of SRC-3 delayed the cell cycle progression of thyroid tumor cells. To ascertain whether the inhibition of cell cycle progression was mediated by SRC-3, we prepared thyroid tumor cells from TRβPV/PV mice and knocked down specifically the expression of SRC-3 by means of an siRNA approach (Figures 3c and d). Indeed, in thyroid tumor cells in which the expression of SRC-3 was knocked down, there was a similar increase in the G1/G0 phase (Figure 3b) and decrease in the G2/M phase (Figures 3a and b). Consistent with observations reported by others, these in vivo and in vitro findings suggested that the delay in cell cycle progression is mediated by the lack of SRC-3 and is accounted for, at least in part, the reduced proliferation of thyroid tumor cells in TRβPV/PVSRC-3−/− mice.
To understand further the mechanisms by which the lack of SRC-3 delayed the entry of tumor cells from the G1/G0 phase into the subsequent cell cycles, we analysed the expression of key cell cycle regulators critical for the G1/S-phase transition. Figure 3c shows that the mRNA expression of E2F1, cyclin-dependent kinase (Cdk2), Cdc6 (DNA replication regulator) and Cdc25a phosphatase (S-phase entry regulator) was reduced in thyroid tumor cells deficient in SRC-3. Consistent with findings by others (Louie et al., 2004, 2006), the reduced expression of these positive regulators in the G1/S-phase transition by the SRC-3 knockdown contributed to the G1/G0 arrest induced by SRC-3 deficiency (Figure 3b).
In addition, knockdown of SRC-3 expression also significantly increased the protein levels of negative regulators such as Rb and p27 at the G1/S transition (Figure 3d). It is important to note that there were no changes in the hyperphosphorylated Rb that acts to release the E2F1 to drive the expression of the S-phase transcription factors, further contribute to arrest the cells in the G1/G0 phase. However, the protein levels of p21 were moderately reduced by the knockdown of SRC-3 expression. Taken together, these data further support the notion that SRC-3 could delay cell cycle progression by mediating cell cycle gene expression.
Deficiency of SRC-3 induces apoptosis through regulating Bcl-2 and caspase-3
The decreased tumor growth (Figure 1b) could also be due to increased apoptosis in TRβPV/PV mice deficient in SRC-3. This proposal is based on the observation that SRC-3 acts to increase prostate cancer cell survival by decreasing apoptosis (Zhou et al., 2005). Using immunohistochemical analysis, we therefore examined whether apoptotic activity was increased in thyroid tumors of TRβPV/PVSRC-3−/− mice by first examining the protein abundance of the cleaved active caspase-3. Compared with the staining intensity of the cleaved active caspase-3 in tumor cells of TRβPV/PVSRC-3+/+ (Figure 4Aa), the protein abundance of cleaved active caspase-3 was increased in tumor cells of TRβPV/PVSRC-3−/− mice (arrows in Figure 4Ab). Cells positively labeled with cleaved active caspase-3 were quantified to indicate a 9.5-fold increase in the cleaved active caspase-3 protein abundance in TRβPV/PVSRC-3−/− mice (positive cells/mm2 area=33.2±8.075, mean±s.e.m., n=668) as compared with TRβPV/PVSRC-3+/+ (positive cells/mm2 area=3.5±1.097, mean±s.e.m., n=163). These results indicate an increase in the apoptotic activity of tumor cells deficient in SRC-3, thereby further contributing to reduced tumor growth.
To understand the mechanism underlying the increased apoptotic activity in tumor cells deficient in SRC-3, we evaluated the expression of the proapoptotic gene, caspase-3 as well as the antiapoptotic gene, Bcl-2, in the thyroid of TRβPV/PV mice with or without SRC-3 by real-time reverse transcription–PCR (Figure 4B) and western blot analysis (Figure 4C). These two genes have been shown to be negatively or positively regulated by SRC-3 (Zhou et al., 2005; Yan et al., 2006b), respectively. Analysis by real-time RT–PCR indicates that the mRNA level of Bcl-2 was repressed by 31% in tumor cells deficient in SRC-3 (Figure 4Ba, compare bar 2 with 1). In contrast, caspase-3 mRNA expression was increased 1.9-fold in tumor cells deficient in SRC-3 (Figure 4Bb, compare bar 2 with 1). The protein abundance of Bcl-2 and caspase-3 was also evaluated by western blot analysis (Figure 4C). Consistent with the alterations at the mRNA level, the protein abundance of Bcl-2 was decreased (compare lanes 6–10 with lanes 1–5, upper panel, Figure 4Ca), whereas that of caspase-3 (lanes 6–10 versus 1–5; middle panel, Figure 4Ca) was increased in the thyroid of TRβPV/PV mice deficient in SRC-3. The intensities in the western blots were quantified, normalized to the loading control of protein-disulfide isomerase (PDI, lower panel, Figure 4Ca) and graphed (Figure 4Cb). The quantitative analysis shows that Bcl-2 protein abundance was significantly decreased 41% (left panel, Figure 4Cb), whereas the caspase-3 protein level was significantly increased by 3.3-fold (right panel Figure 4Cb) in the thyroid of TRβPV/PVSRC-3−/− mice as compared with TRβPV/PVSRC-3+/+ mice.
To further confirm that the changes shown above were mediated via SRC-3, we knocked down specifically SRC-3 expression in thyroid tumor cells derived from TRβPV/PVSRC-3+/+ mice using an siRNA approach. Figure 4Da shows that SRC-3 protein levels were reduced by knockdown using siRNA treatment (compare lane 2 with 1). Concomitant with reduced SRC-3 expression, Bcl-2 protein abundance was decreased (Figure 4Db) and caspase-3 was increased (Figure 4Dc). Panel d (Figure 4D) shows the corresponding loading controls using α-tubulin. These results suggest that deficiency in SRC-3 led to a reduction of the antiapoptotic Bcl-2 and an induction of the apoptotic executioner, caspase-3, resulting in increased apoptotic activity to contribute to decreased thyroid tumor growth of TRβPV/PVSRC-3−/− mice.
Deficiency of SRC-3 decreases neovascularization and tumor cell motility in thyroids of TRβPV/PV mice
The histopathological analysis indicated that SRC-3 could significantly delay the occurrence of vascular invasion and subsequent metastasis via hematogenous spread (Figure 2). Vascular endothelial growth factor A (Vegf-A) is known to mediate increased vascular permeability and to induce angiogenesis, vasculogenesis and endothelial cell growth. We therefore compared the expression of the Vegf-A mRNA in thyroids of TRβPV/PVSRC-3+/+ and TRβPV/PVSRC-3−/− mice (Figure 5a). The Vegf-A mRNA level was decreased 40% in thyroids of TRβPV/PVSRC-3−/− mice as compared with that in TRβPV/PVSRC-3+/+ mice (compare bar 2 with 1), indicating that SRC-3 deficiency could suppress neovascularization through downregulation of the Vegf-A expression. The expression of another growth factor, fibroblast growth factor 2, which also plays a role in angiogenesis, was not changed by SRC-3 deficiency (data not shown).
The findings that lack of SRC-3 delayed the metastatic spread to the lung of TRβPV/PV mice also prompted us to evaluate the motility of thyroid tumor cells from TRβPV/PVSRC-3−/− mice. Figure 5b shows that the tumor cells from TRβPV/PVSRC-3−/− mice moved at a significantly slower rate than those derived from TRβPV/PVSRC-3+/+ mice. These results indicate that the lack of SRC-3 decreased cell motility and cell migration, resulting in decreasing metastasis from primary thyroid tumor lesions to distant organs such as the lung. Vegf-A is also known to promote cell migration. Thus, the reduced expression of Vegf-A due to SRC-3 deficiency could account, at least in part, for the reduced cell motility and migration.
The availability of a mouse model of follicular thyroid carcinoma has allowed us to uncover cellular factors that could contribute to carcinogenesis in vivo. With use of this mouse model, the present study identified a receptor coactivator, SRC-3, that participates in the oncogenic process of tumor development. Consistent with reports of diverse roles for SRC-3 in cellular processes, this study found that SRC-3 acted at multiple pathways to affect the thyroid carcinogenesis in vivo. The lack of SRC-3 in TRβPV/PV mice resulted in reduced tumor cell proliferation by prolonging the G1/G0 phase via control of the expression and activities of cell cycle key regulators. The lack of SRC-3 in TRβPV/PV mice led to increased apoptotic activity via increased expression of caspase-3 and decreased expression of antiapoptotic Bcl-2. Furthermore, the decreased expression of Vegf-A in TRβPV/PV mice deficient in SRC-3 could partly account for the decreased cell motility and migration. Taken together, these findings suggest that SRC-3 functions as a tumor promoter in thyroid carcinogenesis via its effects on multiple signaling pathways.
At present, how the deficiency of SRC-3 led to the alterations of the gene expression in TRβPV/PV mice is not clear. However, it has become increasingly apparent that the functions of SRC-3 are not limited to acting as a transcription coactivator of liganded nuclear receptors (Torres-Arzayus et al., 2004; Zhou et al., 2005; Yan et al., 2006b). For example, it was shown that prostate cancer cell proliferation requires SRC-3 for transitioning cells from the G1/G0 phase to the S phase (Zhou et al., 2005). However, this SRC-3-dependent cell cycle progression occurred in both the presence and the absence of androgens. Furthermore, SRC-3 is also required for prostate cancer cell survival in that when its expression is decreased, the expression of Bcl-2 is decreased and apoptosis increased. These changes were postulated to involve the AKT signaling and/or the nuclear factor-κB pathway (Wu et al., 2002; Zhou et al., 2005). In line with these observations, we have previously shown that SRC-3 modulates the growth of thyroid via the IGF-1-phosphatidylinositol 3-kinase-AKT-mTOR pathway, independent of thyroid hormone (Ying et al., 2005). Thus, the present study further supports the idea that the oncogenic actions of SCR-3 encompass more than acting as a coactivator of nuclear receptor transcription. Clearly, future work is needed to elucidate how SRC-3 integrates its diverse cellular actions in carcinogenesis.
It is important to note that the present study shows that SRC-3 was also required for thyroid tumor cell proliferation and survival. The SRC-mediated alterations in the expression profiles of key regulators in the G1/S-phase transition and apoptotic process in the thyroid tumors were similar to those of prostate cancer cells (Zhou et al., 2005). The similar dependency of SRC-3 for cancer cell growth and survival in two different cancer organs (that is, thyroid and prostate) suggests that the role of SRC-3 in cancer biology could be more critical than previously envisioned. The in vivo findings that lack of SRC-3 delayed thyroid tumor progression and reduced distant metastasis in TRβPV/PV mice suggests that SRC-3 per se is a potential therapeutic target. The therapeutic opportunities are increased by the demonstration that oncogenic actions of SRC-3 involve signaling pathways mediated by phosphorylation cascades of membrane receptors and effectors (Ying et al., 2005; Yan et al., 2006a) as kinase inhibitors are increasingly being developed and expanded. The availability of the TRβPV/PV mouse model of thyroid cancer will allow for testing of these possibilities.
Materials and methods
TRβPV mice have a mixed background of 129Sv X C57BL strains and SRC-3 null mice have a similar mixed background of 129Sv X C57. Mice with mixed genders were used in the analysis.
For thyroids, morphological evidence of hyperplasia, capsular invasion, vascular invasion and anaplasia were routinely counted in the hematoxylin and eosin-stained sections as described (Kato et al, 2006). An interpretation of capsular invasion required the presence of a clear collection of thyroid epithelial cells external to a clearly discernable capsule, usually in a collagenous stroma, and vascular invasion required the presence of a cluster of epithelial cells within the confines of an endothelial-lined vascular channel. Similarly, examination of lung metastases was performed on single sections from each animal and any clear example of thyroid epithelial cells present in the lung was sufficient to interpret this as metastatic, although most cases with metastases had multiple metastatic sites within the lung parenchyma.
Transfection, cell cycle analysis and cell motility assay
Thyroid tumor cells derived from TRβPV/PV thyroid were cultured similarly as described (Kato et al., 2006). SRC-3-specific siRNA (80 μ M, Dharmacon, Lafayette, CO, USA) was transfected into cells using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA). Cell cycle analysis and cell motility assay were carried out similarly as described (Kim et al., 2007). Preparation of primary thyroid cells from fresh tissues was described before (Ying et al., 2003b).
Quantitative real time RT–PCR
The QuantiTect SYBR green RT–PCR kit (Qiagen) was used as per the manufacturer's instructions. Primers for GAPDH (Ying et al., 2005), Vegfa (Kim et al., 2007), and caspase-3 (Kato et al., 2006) have been described previously. The primer sequences of other genes were provided as Supplemental data.
Western blot and immunohistochemistry
Primary antibodies for cyclin D1, Rb, p21, p27, caspase-3, PDI and α-tubulin were described previously (Furumoto et al., 2005; Kato et al., 2006). Anti-SRC-3 antibodies were a gift from Ray-chang Wu (Baylor College of Medicine). Cleaved caspase-3 was detected via immunohistochemistry, and the morphometric quantitation was carried out as described before (Kato et al., 2006). Band intensities were evaluated using NIH IMAGE Software (ImageJ 1.34s; http://rsb.info.nih.gov/ij).
All statistical analysis was carried out using StatView 5.0. (SAS Institute Inc.). Kaplan–Meier analysis and log-rank (Mantel–Cox) test were used for survival analysis; a two-way contingency table was used for histological evaluation; analysis of variance was used for thyroid weight analysis and Student’s t-test was used for analysis of mRNA and protein expression, cell cycle distribution and motility.
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We thank B O’Malley for SRC-3 null mice and R Wu for the anti-SRC-3 antibodies. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
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Ying, H., Willingham, M. & Cheng, SY. The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer. Oncogene 27, 823–830 (2008). https://doi.org/10.1038/sj.onc.1210680
- thyroid carcinogenesis
- cell cycles
- thyroid hormone receptor mutant
- mouse model of thyroid cancer
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