|Year : 2014 | Volume
| Issue : 7 | Page : 102-107
Aurora-A kinase: Potential tumor marker of osteosarcoma
Xiaozhong Zhu, Jiong Mei, Zhiyuan Wang
Department of Orthopedic Surgery, Tongji Hospital, Tongji University, Shanghai 200065, China
|Date of Web Publication||29-Nov-2014|
Department of Orthopedic Surgery, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai 200065
Source of Support: None, Conflict of Interest: None
Aurora kinase family is a group of serine/threonine protein kinase. It is the main regulator in mitosis, including centrosome regulation, spindle formation, and chromosome separation. Aurora-A is an oncogene that is highly expressed in various human tumors, including osteosarcoma. Its high expression level and malignance and tumor metastasis are correlated. Aurora-A is a potential tumor marker. The progress of Aurora-A kinase in tumor research is summarized in this article.
Keywords: Aurora-A kinase, biomarker, oncogene, osteosarcoma, prognosis
|How to cite this article:|
Zhu X, Mei J, Wang Z. Aurora-A kinase: Potential tumor marker of osteosarcoma. J Can Res Ther 2014;10, Suppl S3:102-7
| > Introduction|| |
Osteosarcoma (OS) is the most commonly diagnosed primary malignant bone tumor among children and adolescents. Approximately 75% of OS patients are between 15 and 25 years old. , OS mostly occurs in the metaphysis of long bones, with the distal femur and proximal tibia accounting for more than 50% of all cases. , It is highly invasive, and numerous patients are diagnosed with metastasis. Surgical techniques and chemotherapy are commonly and efficiently used in OS treatment.  The 5 years survival rate is 60-70% for patients with localized OS, and the prognosis is poor for patients with metastasis due to recurrence and chemoresistance. ,, Tumor biomarkers demonstrate their usefulness in diagnosis and prognosis as well as estimating curative effect. Increasing number of studies has been focusing on the molecular mechanisms of OS and has been providing insights for the development and investigation of new targeted therapeutic strategies and the identification of novel tumor biomarkers. ,,
Aurora kinase family is a new group of serine/threonine protein kinase. It regulates the centrosome and microtubule function. It is involved in multiple events, including centrosome replication and separation, spindle microtubule assembly and stabilization, and chromatin condensation and congression. It plays an important role in normal mitosis by executing various mitoses and maintaining the integrity of the genome. ,,, Aurora kinase family has three members, namely, Aurora-A (Aurora 2), Aurora-B (Aurora l), and Aurora-C (Aurora 3), in mammalian cells until date. 
Aurora-A, also called BTAK, is an important member of the Aurora kinase family. Related studies show that Aurora-A gene is highly expressed in some solid tumors, such as breast,  ovarian,  esophageal,  colon,  lung,  and bladder  cancers, as well as OS.  Inhibiting Aurora-A kinase activity can effectively block the growth and cell proliferation as well as induce OS cancer cell apoptosis.  Research suggests that the expression of Aurora-A is strongly correlated with some tumor biology behaviors, which also have certain prediction effects on the prognosis of some tumors. 
Aurora-A is an oncogene  that can phosphorylate a wide variety of tumor-associated protein substrates, including protein phosphatase 1 (PP1), RASGAP, TPX2, Ajuba, p53, and CDH1, which are involved in the occurrence and development of tumor. ,, Moreover, the overexpression of Aurora-A can destroy the activating effect of taxol or nocodazole on spindle checkpoint, thus inducing tumor drug resistance.  At present, Aurora-A kinase is a new target for tumor treatment that has been gradually recognized. Research and application of its small molecule inhibitors, especially combined with chemotherapy drugs, has become a new direction for malignant tumor treatment. The current article summarizes the recent advancements on the biological functions of Aurora-A kinase and its relationships with tumors, especially OS.
| > Biological functions of Aurora-A|| |
Aurora-A is a key kinase encoding gene located in the 20ql3.2.  The region has common amplification in human malignant tumor, such as colon, ovarian, gastric, breast, and esophageal cancers. Aurora-A, known as BTAK as well as Aurora 2, AIK1, AURKA, STK15, STK6, and HsAIRK1, was first detected in the breast cancer tissue.  It is composed of 403 amino acids, with two domains, namely, a variable region and a C-terminal catalytic region. The amino acid sequence of the catalytic region is highly conserved. The catalytic region contains an activation loop, which participates in regulating Aurora-A kinase activity, and a destruction box (Dbox), which is involved in Aurora-A kinase degradation. The variable region is located in the N terminal, which has three boxes. These boxes are associated with the intracellular localization of Aurora-A and the recognition and combination with proteins related to centrosome. Abox is also responsible for activating the degeneration function of Dbox. ,,
The mRNA and protein levels of Aurora-A are minimal during the G1 and S phases, peak during the G2 and M phases, and then drop rapidly after the end of the M phase. Aurora-A kinase is activated during the conversion from G2 to M phase and reaches the maximum activity during early mitosis. Aurora-A begins to spread over the centrosome at the end of the S phase and modifies the centrosome, by which time the centrosome has finished replication. When the centrosome begins replicating, Aurora-A kinase becomes undetectable in the cells. Therefore, Aurora-A is indirectly involved in centrosome replication.  However, several studies have found that the abnormal expression of Aurora-A activates centrosome amplification and is independent of the Aurora-A kinase activity. Aurora-A plays a key role in establishing and maintaining bipolar spindle.  Inhibiting Aurora-A activity can result in the formation of unipolar spindle, but bipolar spindle is the premise of the correct separation of chromosome.  For example, the Aurora-A inhibitor MLN8237 affects multiple mitotic processes in human OS U2OS cells. , Another study shows that bipolar spindle is formed in human tumor cells that lack Aurora-A, but chromosomes cannot be arranged on the equatorial plane, which can be attributed to the aggregation of microtubules or interaction error of kinetochore with microtubules. ,
Aurora-A plays an important role in various mitoses and the formation of by-products because of the consumption of Aurora-A during mitosis. , Hence, the selective inhibition of Aurora-A will have a profound effect on anti-mitosis.
| > Relationship between Aurora-A kinase and tumors|| |
The overexpression of Aurora-A can promote the formation of malignant tumors. The overexpression frequency of mRNA and the protein of Aurora-A is high in various tumors but unrelated to the amplification of its gene. For example, mRNA and the protein expression of Aurora-A are more than 60% of the hepatocellular carcinoma, but the amplification of Aurora-A gene can only be detected in 3% of them. This manifestation has also been reported in breast and gastric cancers. ,, Therefore, the overexpression of Aurora-A may be adjusted not only by gene amplification, but also by other mechanisms, such as transcriptional activation and inhibition on protein degradation. Aurora-A kinase is also involved in the growth of human OS SAOS-2 and U2OS cells, and prohibiting Aurora-A kinase activity can prevent tumor cell growth by inducing apoptosis and G2/M cell cycle arrest. 
Aurora-A can play its role through phosphorylating various substrates, for example, Aurora-A can directly bind to the aa1314-18p53 region of breast cancer associated gene 1 (BRCA1) and phosphorylate the Ser308 locus of BRCA1 during early mitosis, thus affecting the cell cycle. , Aurora-A can also phosphorylate the Ser315 locus of p53 and promote MDM2-mediated p53 degradation.  Aurora-A can also phosphorylate the Ser215 locus of p53 and reduce the transcription activity of p53, thus regulating the tumor suppressor function of p53.  p53 can inhibit the cancer gene activity of Aurora-A for feedback, and this effect can be blocked by TPX2. , Hence, the interaction between Aurora-A kinase and p53 can play an important role in the occurrence and development of malignant tumor. The phosphorylation of Akt Ser473 and mTOR Ser2448 is increased in the MMTV-Aurora-A transgenic mice, proving that Aurora-A can regulate mTOR signaling pathways.  Aurora-A can also regulate the following substrates: CPEB, Eg5, TACC, Ajuba, TPX2, CENP-A, and PP1. ,,, Most of the relationships between Aurora-A and these proteins are mutual adjustment. For example, PP1 can lead to the dephosphorylation of Aurora-A and reduction of its enzyme activity;  TPX2 can activate Aurora-A, and the triggered Aurora-A spreads to the spindle during mitotic phase;  and Ajuba can activate Aurora-A and promote cells enter the mitotic phase. 
Malignant tumors with heteroploid are generally more serious than malignant tumors with diploid. Aurora-A is clearly correlated with the heteroploid of malignant tumors.  It can promote the formation of heteroploid in two major ways, that is, cytoplasmic fault and the formation of the mitotic spindle. The mitosis is terminated by activating the spindle checkpoint, thus forming heteroploid. Therefore, abnormal Aurora-A and the pathologic features, a clinical stage, and prognosis of malignant tumors may be correlated. However, results from different tumors vary. , The gene polymorphism (Phe31Ile and Val57Ile) of Aurora-A is closely associated with human tumor susceptibility, and the Ile31 allele of Phe31Ile is amplified in human breast, prostate, and lung cancers. ,, A large perspective case-control study showed that if Phe31Ile and Val57Ile polymorphisms coexist, not only the risk of breast cancer is increased by two-fold, especially in postmenopausal women, but also the probability of patients to suffer from invasive breast cancer is increased.  Another report showed that the polymorphism of Val57Ile is closely associated with the progression of gastric cancer, whereas the polymorphism of Phe31Ile is closely linked to the susceptibility of gastric cancer. ,
| > Correlation between Aurora-A and p53 gene|| |
Aurora-A and p53 gene can regulate each other. p53 can directly bind to the Aurora-box at the N-terminal of Aurora-A, and this bond inhibits Aurora-A kinase activity, suppresses centrosome amplification induced by Aurora-A, and blocks the ability of Aurora-A to transform NIH3T3 cells.  Aurora-A can phosphorylate the 315 locus of p53, making it degrade via the ubiquitin-proteasome pathway,  which is an important mechanism of p53 inactivation.  p53 (+/−) mutant mice with MMTV-Aurora-A transgene  developed cancer within 6 months, and 70% of the mice had cancer in the 18 th month. The carcinogenic time and rate were obviously higher than the transgenic mice without p53 (+/−) mutations. No tumor was observed in 15 p53 (+/−) mice with matching months of age.  Thus, p53 (+/−) mutation promoted the carcinogenicity of highly expressed Aurora-A in breast cells. Zhang et al.  found that the high expression of Aurora-A does not induce tumor formation in animal models, but increases p53 accumulation and p53-dependent apoptosis. Does it mean that the carcinogenicity of Aurora-A is achieved through p53 degradation? Neither obvious increase of p53 protein nor apoptosis was observed in transgenic model mice with MMTV-Aurora-A. This result can be attributed to balance because genetic instability induced by Aurora-A activates p53, whereas the high expression of Aurora-A maintained by progestogen leads to p53 degradation.
| > Correlation between Aurora-A and Breast cancer associated gene 1 gene|| |
Breast cancer-associated gene 1 is a specific gene in breast and ovarian cancers. It is located in the centrosome and plays an important role in regulating centrosome number. Under physiological condition, the combination of Aurora-A and BRCA1 may lead to BRCA1 S308 phosphorylation, which promotes a transition from G2 to M phase.  When BRCA1 is mutated to BRCA1-S308N, Aurora-A is unable to phosphorylate BRCA1.  Most of BRCA1 mutations are frame-shift or meaningless mutations because function-related RING domain and E3 ubiquitin ligase maintain integrity. BRCA1 ubiquitin ligase directly inhibits the centrosome-dependent microtubule nucleation during the S phase, but centrosome microtubule nucleation is increased by five-fold and the BRCA1 level peaks during the M phase.  Sankaran et al.  found that the inhibition of BRCA1-dependent centrosome microtubule nucleation is higher during S phase than M phase because the centrosome during the M phase is not primarily regulated by BRCA1. Increased Aurora-A during the M phase decreases the activity of BRCA1 E3 ubiquitin ligase, thus reducing the BRCA1-induced inhibition of centrosome microtubule nucleation. Through dephosphorylation by PP1α, the activity of BRCA1 E3 ubiquitin ligase is strengthened and further inhibits the nucleation ability of centrosome microtubules. In this process, BRCA1, Aurora-A, and PP1α form a regulatory ring. During the transition from G2 to M phase, the elevation of Aurora-A inhibits both BRCA1 and PP1, which may lead to obvious centrosome microtubule nucleation. However, in the latter phase of mitosis, the functions of BRCA1 and PP1 are recovered with Aurora-A degradation. PP1 inhibits Aurora-A function and is also regulated by cdc2, cdc25, and Aurora-A.
| > Correlation between Aurora-A and PTEN/PI3K/AKT signaling pathway|| |
An MMTV-Aurora-A transgenic mouse model  was used to demonstrate that heteroploid cells induced by increased Aurora-A survive apoptosis and form tumor probably because the PTEN/PI3K/AKT signaling pathway was activated. In the 4 th month, pAKT was higher in the breast tissues of transgenic mouse than that of the control group but was significantly increased in the breast of pregnant or multiparity mice. Both the phosphorylated AKT and the downstream genes of AKT, such as mTOR and GSK-3 β, were elevated. Moreover, the cyclin D1, which is related to pAKT and GSK-3 β, was also raised. Hence, the activation of PTEN/PI3K/AKT signaling pathway may cause tetraploid cell hyperplasia. The pAKT level is equal in MMTV-Aurora-A and MMTV-Aurora-A p53 (+/−) mice. Therefore, AKT phosphorylation is not induced by p53. The Ras/Raf/MEK/ERK/MAP signaling pathway may be involved in the carcinogenicity of Aurora-A in pancreatic cancer. ,
| > Correlation between Aurora-A and gene polymorphism of Aurora kinase|| |
The F31I and V57I of Aurora-A are two common regions of gene polymorphism. A total of 941 cases of breast cancer patients were compared with 830 cases of control individuals.  The comparison showed that the carriers of homozygous I31/V57 (AA + GG genotype) have a higher risk of breast cancer by 60%, which was evident in postmenopausal women (odds ratio [OR] =1.96), than the normal genotype (TT + GG). The polymorphisms of functional F31I and risk factors related to the estrogen of breast cancer have no obvious interactions. The breast cancer risk in combined high-risk genotype I31/V57 is not higher than that in the reference genotype F31/I57, which may be due to the low proportion of the high-risk genotype in this group. However, Cox et al.  found that the polymorphism of Aurora-A gene F31I is related to breast cancer in the United States. In the east crowd, , the Ile31 alleles of Aurora-A gene are associated with high risk of breast cancer, especially in overweight postmenopausal women, and the positive correlation changes with long-term exposure to a high level of estrogen in vivo. Ile/Ile genotype is 40% in Chinese,  which is higher than that in Caucasians (6%). However, the proportion of codon 57 in Chinese and Caucasians is the same. When both Ile31 and Ile57 alleles are present, the breast cancer risk is higher than homozygous Phe31 and Val57 alleles by 40% but not statistically significant. The amplification of Aurora-A in breast cancer is only 12-18%, and the excessive expression of protein is >90% probably because genes have been upregulated by estrogen in the breast tissue. In addition, the Ile/Ile genotype of Chinese is seven-fold higher than that of Caucasian, but breast cancer cases are significantly lower among Chinese than Caucasians, which can be attributed to other factors that attenuate the carcinogenicity of Ile/Ile genotype, such as environmental factors and gene polymorphisms.
Is the polymorphism of Aurora-A gene F31I related to the risk of breast cancer? Ewart-Toland et al.  collected case-control data from 10 independent cases, including colon, breast, prostate, skin, lung, and esophageal cancers, and analyzed the polymorphism of F31I. A meta-analysis was provided with five additional published articles.
In a study of 9549 cases and 8326 controls, the heterozygote T + 91A (OR = 1.10, P = 0.006) and the homozygote T + 91A (OR = 1.40, P < 0.001) significantly increase the risk of cancer. In a meta-analysis of four breast cancer cases, only homozygous T + 91A enhances the risk of cancer (OR = 1.35). Moreover, 9 of 10 independent studies show trends or borderline significance of the homozygous T + 91A.
Fletcher et al.  performed meta-analyses. Most of the nonselective cases are patients with unilateral breast cancer, that is, without family history of breast cancer. Thus, they compared medical records of 507 bilateral breast cancer patients with 875 population-based control subjects to confirm the roles of gene polymorphisms in breast cancer. The OR of homozygous Ile/Ile to develop bilateral breast cancer is 0.63, which is consistent with the risk of unilateral breast cancer (OR = 0.79).
Moreover, five articles about meta-analyses of the relationship between the polymorphism of Aurora-A gene F31I and breast cancer together and their own data were published before 2005. ,,,, The results significantly vary. Only one of the five articles suggests a strong linkage between the two indexes. The other four articles show a negative result, and three of these articles conducted the same meta-analysis. ,,
| > Aurora-A may be the early events of carcinogenesis|| |
Aurora-A may be the regulator of ductal carcinoma in situ (DCIS) to invasive carcinoma transition, which is an early event of breast cancer. High expressions of Aurora-A in breast cancer adjacent ductal epithelium, DCIS, and invasive ductal carcinoma are 78%, 70%, and 32% respectively.  Aurora-A gene AA + GG carriers do not have a higher risk of invasive breast cancer (OR = 1.45), but the risk of carcinoma in situ is nearly three-fold (OR = 2.93).  The gene amplification of Aurora-A in breast cancer mice  and overexpression of Aurora-A in human ovarian cancer  are both early events.
In MMTV-Aurora-A transgenic mice, the Aurora-A gene includes breast epithelial centrosome abnormalities and gene instability, which lead to breast cancer.  However, some studies contradict these results.  For instance, Aurora-A is lowly expressed in normal tissue and DCIS but highly expressed in invasive carcinoma. Li et al.  demonstrated that 100% of the mice developed mammary gland tumor (MGT) within 3-6 months after August/Copenhagen/Irish mice were treated with estrogen. In addition, 30% of the centrosome demonstrated the amplification in atypical hyperplasia after 3 months of treatment with E2 (17 beta-estradiol), whereas 38% of the centrosome showed amplification in DCIS in the 4 th month. However, centrosome amplification in MGT exceeded 90%, whereas centrosome hyperplasia in catheters without the typical hyperplasia was <7%. Hence, centrosome amplification is an early event of MGT. The molecular changes of MG obtained through E2 treatment and MGT before heteroploid development are similar to the molecular changes before the early infiltration of human sporadic breast cancer. After 4 months of E2 treatment, the mRNA and protein levels of Aurora-A in MG are both elevated to the levels in MGT. Therefore, the high levels of Aurora-A in DCISs may be the early critical event of MGT development.
| > Correlation between Aurora-A and diagnosis|| |
Nadler et al.  analyzed 638 cases of breast cancer with a follow-up after 15 years and found that the high expression of Aurora-A is closely related to low survival rate (P = 0.0005). This correlation was significant in both whole cases and patients with negative lymph nodes. Moreover, the high expression of Aurora-A is obviously associated with high nuclear grading, high expression of HER-2/neu, and PR. In multi-factor analysis, the high expression of Aurora-A, tumor size larger than 2 cm, ER status, and positive lymph nodes were all independent prognostic factors. The authors also found that Aurora-B lacks such predictive prognostic value. The details of these data should be pointed out. First, the cases were collected between 1962 and 1980. Patients with negative lymph nodes did not undergo chemotherapy, whereas 15% of patients with positive lymph nodes received chemotherapy. Cases after 1978 accounted for 27% of all cases, and these patients received tamoxifen therapy. Therefore, the disease history was longer, and the treatment principles were different from those applied today. Second, a new method called traditional pathological scoring was adopted. It is different from automated quantitative analysis. No relapse was observed in Aurora-A positive and negative groups in 112 breast cancer patients with 31% negative lymph nodes. The survival rate (P = 0.34) and overall survival rate (P = 0.42) had no significant difference, but a critical correlation between nuclear grading and Aurora-A (P = 0.05) was observed.  Royce et al.  postulated that the differences may be related to different sample sizes, the proportion of patients with negative lymph nodes, and methods for calculating the Aurora-A protein expression. The differences may also be related to lower death and relapse of this group of cases during the follow-up period. Moreover, Aurora-A is an early, rather than advanced, event in breast cancer. Nadler et al.  thought Aurora-A is a beneficial complement for the traditional pathology index, which can help distinguish patients with poor prognosis from patients with negative lymph node. The high expression of Aurora-A in early breast cancer needs a positive treatment.
| > Summary and perspective|| |
Aurora kinases are closely related with various cancers. However, investigations on the role of Aurora-A in OS are few. Aurora-A gene was firstly isolated from tumor.  It successfully induces cancer.  The expression of Aurora-A and/or Aurora-B is common in several tumors, with an expression rate of 26-94%. The high expression of Aurora-A is also an independent prognostic indicator associated with prognosis. Therefore, Aurora-A is one of the potential tumor markers of OS. However, further investigations are needed.
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