Secondary Logo

Journal Logo

Elevated Expression of Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) Is Associated With a Poor Prognosis in Osteosarcoma

Matsuda, Kotaro MD, PhD; Miyoshi, Hiroaki MD, PhD; Hiraoka, Koji MD, PhD; Hamada, Tetsuya MD, PhD; Nakashima, Kazutaka MT; Shiba, Naoto MD, PhD; Ohshima, Koichi MD, PhD

Clinical Orthopaedics and Related Research®: September 2018 - Volume 476 - Issue 9 - p 1848–1855
doi: 10.1097/CORR.0000000000000379
CLINICAL RESEARCH
Free

Background Transforming acidic coiled-coil containing protein 3 (TACC3) is expressed during the mitotic phase of nuclear division and regulates microtubules. Recently, high TACC3 expression in tumor cells of various cancers including soft tissue sarcoma has been reported. However, its role in osteosarcoma remains unknown. Because we have few prognostic markers for survival in osteosarcoma, we wanted to investigate the potential role of TACC3 in human osteosarcoma and determine if it is associated with survival.

Questions/purposes (1) Is there a relationship between TACC3 expression and clinicopathologic characteristics such as sex, age (< 20 or ≥ 20 years), histologic type (osteoblastic or others), tumor location (femur or others), American Joint Committee on Cancer staging system (AJCC stage IIA or IIB), tumor necrosis percentage after chemotherapy (< 90% or ≥ 90%), p53 expression (low or high), and Ki-67 expression (low or high)? (2) Is TACC3 expression associated with event-free and overall survival in patients with osteosarcoma?

Methods Forty-six conventional patients with osteosarcoma were treated at our institution from 1989 to 2013. Patients were excluded because of unresectable primary site (two patients) and no chemotherapy (two patients). Patients with metastasis at the initial visit (five patients), without pretreatment biopsy samples (two patients), or clinical charts (two patients) were also excluded. The left 33 patients who received neoadjuvant and adjuvant chemotherapy, which consisted of cisplatin/doxorubicin/methotrexate or cisplatin/doxorubicin/methotrexate/ifosfamide, and completed surgical resection with histologic wide tumor margins. Primary tumor samples before chemotherapy were used in this study. We investigated TACC3 expression using immunohistochemical staining and statistically analyzed the TACC3 expression, clinicopathologic characteristics, and event-free and overall survival in patients with osteosarcoma.

Results High TACC3 expression was observed in 19 of 33 osteosarcoma specimens (58%), and this was associated with larger tumor size (ie, AJCC stage IIB in this study; p = 0.002), higher p53 expression (p = 0.007), and higher Ki-67 expression (p = 0.002). The estimated metastasis-free survival at 5 years was 21% (95% confidence interval [CI], 7%–41%) in patients with high TACC3 expression and 79% (95% CI, 47%–93%) in patients with low TACC3 expression (p < 0.001), and the estimated overall survival at 5 years was 34% (95% CI, 13%–56%) in patients with high TACC3 expression and 86% (95% CI, 54%–96%) in patients with low TACC3 expression (p < 0.001). Furthermore, high TACC3 expression was an independent poor prognostic factor for metastasis-free survival with a hazard ratio of 3.89 (95% CI, 1.07–19.78; p = 0.039) as well as overall survival with 4.41 (95% CI, 1.01–32.97; p = 0.049).

Conclusions High TACC3 expression was associated with aggressive clinicopathologic features and unfavorable prognosis in these patients with osteosarcoma. Our preliminary results suggest that further analysis about mutation or an inactive form of TACC3 would be useful to understand the mechanism of abnormal TACC3 expression in patients with osteosarcoma. If these findings are substantiated in larger studies, TACC3 might be useful for predicting survival and a potential therapeutic target for osteosarcoma.

Level of Evidence Level III, therapeutic study.

K. Matsuda, H. Miyoshi, K. Nakashima, K. Ohshima, Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan

K. Matsuda, K. Hiraoka, T. Hamada, N. Shiba, Department of Orthopedic Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan

H. Miyoshi, Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan, email: miyoshi_hiroaki@med.kurume-u.ac.jp

Each author certifies that neither he nor any member of his immediate family has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his institution approved approval for the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

Received December 16, 2017

Accepted May 23, 2018

Back to Top | Article Outline

Introduction

Osteosarcoma is the most common primary malignant bone tumor in adolescents and occurs most frequently in long bones, especially around the knee [20]. Additionally, it is aggressive and often metastasizes to the lungs. Despite advances in multimodal therapy, the 5-year survival of osteosarcoma is approximately 60% to 70%, which has remained stagnant over the past three decades [3]. Patients with metastases have an especially poor prognosis; approximately 20% succumb to their tumors within 5 years [10]. Current standard treatment for osteosarcoma includes wide resection with chemotherapy based on combinations of cytotoxic agents such as cisplatin, doxorubicin, and methotrexate. When conventional treatment is insufficient, there are few other options available [12]. Therefore, treating osteosarcoma remains very challenging.

Transforming acidic coiled-coil containing protein 3 (TACC3) is a member of the TACC family located in the 4p16.3 region of chromosomes [5]. TACC3, a target of Aurora A kinase, contributes to microtubule/centrosome stability during mitosis [18]. This structure forms a mitotic spindle to separate the chromosomes. Thus, microtubule/centrosome dysfunction results in chromosomal instability [24]. Abnormal TACC3 expression is associated with various cancers [6]. In addition, it has been shown that TACC3 depletion induces p53-mediated apoptosis [23]. Despite the recent development of chemotherapeutic agents targeting mitotic proteins such as Aurora kinase and Polo-like kinase, which have been tested for acute lymphocytic leukemia, small and nonsmall cell lung cancer, and colorectal cancer, their effects remain unclear [9]. Therefore, TACC3, an Aurora A kinase target, is a potential therapeutic target for patients with osteosarcoma.

The relationship between high TACC3 expression in tumor cells and poor prognosis has been shown in several cancers, including soft tissue sarcomas as authors previously described [11, 15, 19, 21, 36, 37]. However, the association between clinicopathologic features and TACC3 expression as well as the potential importance of this protein with respect to survival in patients with osteosarcoma to our knowledge has not been reported.

We therefore asked: (1) Is there a relationship between TACC3 expression and clinicopathologic characteristics such as sex, age, histologic type, tumor location, American Joint Committee on Cancer (AJCC) staging system, tumor necrosis percentage after chemotherapy, p53 expression, and Ki-67 expression? (2) Is TACC3 expression associated with event-free and overall survival in patients with osteosarcoma?

Back to Top | Article Outline

Patients and Methods

Fifty-one patients with newly diagnosed osteosarcoma have been treated at Kurume University since 1989. Low-grade osteosarcoma (five patients) was excluded from this study. Patients without pretreatment biopsy samples (two patients) or clinical charts (two patients) were excluded. Other patients were excluded because of an unresectable primary site (two patients) and no chemotherapy (two patients). Of the 38 patients, five with metastasis at the initial visit were excluded. This study included pretreatment biopsy samples of 33 patients with primary high-grade conventional osteosarcoma who were diagnosed and treated at our institution from 1989 to 2013. All patients received the standard therapeutic protocol, including neoadjuvant and adjuvant chemotherapy, which consisted of cisplatin/doxorubicin/methotrexate or cisplatin/doxorubicin/methotrexate/ifosfamide [13, 31], and complete surgical resection with histologic wide margins. They were evaluated by clinical examination and plain radiographs and CT scans at least every 3 months after completion of treatment for 2 years, then every 6 months for at least 5 years. Two pathologists (KO, HM) reviewed all biopsy specimens according to the 2013 World Health Organization classification [27]. Clinical data were collected from patients’ medical charts by a research assistant (MS) who was not involved in patient care. This retrospective study was approved by the Research Ethics Committee of Kurume University, and written informed consent was obtained according to the Declaration of Helsinki.

A total of 21 males (64%) and 12 females (37%) with a mean age of 17.2 years (range, 5–46 years) were included in this study; 26 tumors (79%) were osteoblastic type, five (15%) were chondroblastic type, and two (6%) were fibroblastic type. In total, 22 tumors (67%) originated in the femur, five (15%) in the tibia, one (3%) in the humerus, three (9%) in the fibula, one (3%) in the radius, and one (3%) in the scapula. According to the AJCC staging system 8th edition [2], there were nine (27%) patients with stage IIA disease and those with stage IIB comprised 24 patients (73%). There were no patients with stage III disease. Tumor necrosis as assessed by the Rosen and Huvos grading system after neoadjuvant chemotherapy [26] was < 90% in 19 patients (58%) and ≥ 90% in 14 patients (42%). Nineteen of 33 patients (58%) experienced metastasis, and 17 (52%) succumbed to their tumors during the followup period (mean, 91.5 months; range, 9–283 months). No patients experienced local recurrence. The minimum followup of patients who did not relapse was 47 months.

Formalin-fixed, paraffin-embedded tissues of 3-µm thickness were deparaffinized and rehydrated with water. Antigen retrieval was performed by heating in a microwave, and then endogenous peroxidase activity was blocked using 3% hydrogen peroxide. Tissue sections were incubated with primary antibodies specific for TACC3 (rabbit monoclonal, clone: EPR7756, ab134154, Abcam, Cambridge, UK, dilution 1/200) for 30 minutes at room temperature, p53 (mouse monoclonal, clone: Do-7, M7001, Dako, Glostrup, Denmark, dilution 1/100), and Ki-67 (mouse monoclonal, clone: MIB-1, M7240, Dako, dilution 1/200) for 1 hour. Samples were then incubated with DaKo REAL™ EnVision™ System (Dako) for 30 minutes at room temperature as the secondary antibody. Visualization of the immunoreaction was performed using diaminobenzidine for 5 minutes.

The assessment of TACC3, p53, and Ki-67 in tumor cells was manually calculated by examining a minimum of 100 tumor cells in five fields using an optical microscope with 400-fold magnification. A tumor cell was defined as TACC3-positive when the cytoplasm was stained according to the criteria of other malignancies [11, 15, 19, 21, 36, 37]. For p53 and Ki-67, nuclear staining was recognized as positive based on the criteria of a previous study [25]. Two independent pathologists (KO, HM) who were blinded to any clinical information evaluated the expression of TACC3, p53, and Ki-67.

TACC3-positive percentages in each case ranged from 0% to 80% (Fig. 1). TACC3-positive tumor cells were observed in 30 of 33 osteosarcoma cases (91%). The cutoff value for TACC3 expression was determined by using the receiver operating characteristic (ROC) curve and Youden index (Fig. 2) [1]. Metastasis (negative or positive) was used as a dichotomous variable, whereas the TACC3-positive rate was a continuous variable. The chosen cutoff value was derived as 20%. Therefore, TACC3-positive percentages of 20% and above were defined as high expression. For p53 and Ki-67, high expression was defined as 10% and above based on the ROC curve and Youden index as well.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

TACC3 was highly expressed in 19 of 33 tumors (58%), and the expression of TACC3 was detected in the tumor cell cytoplasm in all tumors. In addition, TACC3 expression was observed in many mitotic tumor cells. On the other hand, high expression of p53 and Ki-67 was detected in 23 (70%) and 22 of 33 tumors (67%), respectively (Fig. 3).

Fig. 3 A-H

Fig. 3 A-H

Back to Top | Article Outline

Statistical Analysis

Patients were classified by sex, age (< 20 or ≥ 20 years), histologic type (osteoblastic or others), tumor location (femur or others), AJCC staging system (stage IIA or IIB), tumor necrosis percentage after chemotherapy (< 90% or ≥ 90%), p53 expression (low or high), and Ki-67 expression (low or high) based on previous studies [17, 25, 32, 33]. We analyzed clinicopathologic features and TACC3 expression by Fisher’s exact test. Metastasis-free survival was defined as the duration between the day of surgery and the day of the first metastasis; overall survival was defined as the duration between the day of the initial visit and the day of last followup or death. Local recurrence-free survival was not analyzed in this study because there were no patients with local recurrence. We evaluated metastasis-free survival and overall survival using the Kaplan-Meier method and a log-rank test. Multivariate Cox regression analysis was used to assess the effect of possible risk factors on metastasis-free survival and overall survival. A p value < 0.05 was recognized as statistically significant. JMP Version 12 software (SAS Institute, Tokyo, Japan) was used to perform statistical analysis in this study. Sex, age, histologic type, tumor location, AJCC stage, tumor necrosis percentage after chemotherapy, p53 expression, and Ki-67 expression were the prognostic factors for metastasis-free survival and overall survival evaluated by univariate analysis. Of these, AJCC stage IIB, high TACC3 expression, and high p53 expression correlated with a shorter metastasis-free survival as well as overall survival. These three parameters were evaluated by multivariate analysis.

Back to Top | Article Outline

Results

Higher TACC3 expression was associated with larger tumor size (ie, AJCC stage IIB in this study) (p = 0.002), higher p53 expression (p = 0.007), and higher Ki-67 expression (p = 0.002) (Table 1).

Table 1

Table 1

The estimated metastasis-free survival at 5 years was 21% (95% confidence interval [CI], 7%–41%) for patients with high TACC3 expression and 79% (95% CI, 47%–93%) for patients with low TACC3 expression (p < 0.001) (Fig. 4). The estimated overall survival at 5 years of patients with high TACC3 expression was 34% (95% CI, 13%–56%), whereas that of patients with low TACC3 expression was 86% (95% CI, 54%–96%; p < 0.001; Fig. 5).

Fig. 4

Fig. 4

Fig. 5

Fig. 5

After controlling for potentially confounding variables, we found that only high TACC3 expression was associated with a lower likelihood of metastasis-free survival (hazard ratio [HR], 3.89; 95% CI, 1.07–19.78; p = 0.039) (Table 2). In addition, we found that only high TACC3 expression was associated with an increased likelihood of death in patients with osteosarcoma (HR, 4.41; 95% CI, 1.01–32.97; p = 0.049; Table 3).

Table 2

Table 2

Table 3

Table 3

Back to Top | Article Outline

Discussion

The relationship between TACC3 overexpression in tumor cells and poor prognosis has been reported in several malignant tumors such as esophageal squamous cell carcinoma, nonsmall cell lung cancer, hepatocellular carcinoma, gastric cancer, and soft tissue sarcoma [11, 15, 19, 21, 36, 37]. However, little is known about the association of TACC3 overexpression in osteosarcoma with patients’ clinicopathologic features and outcome. Therefore, we assessed the potential of TACC3 as a prognostic predictor for osteosarcoma and found an association of TACC3 overexpression with metastasis-free survival and overall survival in a small group of patients with osteosarcoma.

There are some limitations of our results. First, the number of patients in this study was relatively small. In addition, not all patients with osteosarcoma had sufficient followup duration or complete enough records to analyze; there may have been transfer bias. The problem with having a small cohort is weakness of the ability to perform a valid multivariate analysis, which needs a large cohort. It was unusual that tumor necrosis after chemotherapy was not associated with prognosis. Second, immunohistochemical (IHC) analysis was the sole method of assessing TACC3 expression. Because TACC3 is involved in microtubule regulation, the expression of TACC3 should be expected in all cells undergoing mitosis. So, the IHC antibody may also mark abnormally expressed TACC3. Hence, we performed polymerase chain reaction-based TACC3 copy number assay to measure the association of TACC3 expression with gene amplification. However, we could not find the correlation between TACC3 protein expression and gene amplification (data not shown). More detailed analysis of a mutation or IHC target such as an inactive form of TACC3 would be necessary to solve the question of how TACC3 is abnormally expressed in patients with osteosarcoma.

TACC3 expression was observed in many mitotic tumor cells by IHC analysis. This is consistent with previous observations that TACC3 is expressed, especially in the mitotic phase [5, 6]. However, IHC analysis also detected TACC3 in nonmitotic tumor cells. In normal human tissues, TACC3 is expressed in highly proliferative tissues such as the testes, spleen, thymus, and peripheral blood lymphocytes [23, 28]. Additionally, it was reported that TACC3 expression is associated with the proliferative activity of hepatocellular carcinoma cells [21]. In our study, higher TACC3 expression was correlated with that of Ki-67. This marker is expressed in the nuclei throughout the cell cycle, except for the G0 phase, and reflects the cell’s proliferative ability [4]. These findings suggest that TACC3 is expressed in tumor cells with proliferative potential as well as in mitotic tumor cells. TACC3 expression was correlated with increased p53 expression, but with the number of patients we had, we could not show an association with high p53 expression and poor prognosis in this study. Opinions are divided regarding the relationship between high p53 expression and poor prognosis in patients with osteosarcoma, whereas many reports have demonstrated that high p53 expression is an indicator of poor prognosis in this disease [14].

Patients with high TACC3 expression had shorter metastasis-free survival and overall survival compared with patients with low TACC3 expression. Furthermore, after controlling for likely confounding variables, we found that high TACC3 expression was associated with an increased likelihood of metastasis and death in patients with osteosarcoma. There are several possible explanations for this. First, TACC3 upregulation could activate the PI3K/AKT and ERK signaling pathways, which promotes epithelial-mesenchymal transition. Epithelial-mesenchymal transition provides tumor cells with migratory ability and increases their invasive capacity [8]. In our study, higher TACC3 expression was correlated with larger tumor size (ie, AJCC stage IIB in this study). The IIA and IIB subdivision in the AJCC stage is useful for predicting a subsequent metastatic event [16]. Second, higher levels of TACC3 could decrease DNA repair ability, resulting in genomic instability [7]. However, it is possible that p53-mediated apoptosis might not occur because the p53-dependent checkpoint of tumor cells may be compromised in the TACC3 (high)/p53 (high) group as in nonsmall cell lung cancer [15].

Several studies have demonstrated the relationship between high TACC3 expression in tumor cells and poor prognosis in various cancers [11, 15, 19, 21, 36, 37]. However, there is no consensus regarding the cutoff value for high TACC3 expression based on IHC analysis. Therefore, we determined the cutoff value for TACC3 expression by analyzing the ROC curve and Youden index using metastasis, an established indicator of osteosarcoma prognosis [33], as a dichotomous variable as well as TACC3 positivity rates as the continuous variable. In addition, the cutoff value for p53 and Ki-67 expression was also defined based on the ROC curve and Youden index. Our cutoff value using the ROC curve, and not an arbitrary value, is considered appropriate [1].

It has been reported that TACC3 disruption suppresses tumor growth without damaging normal cells [35], induces premature senescence in tumor cells [29], and increases the susceptibility of tumor cells to paclitaxel, which is a microtubule inhibitor [30]. In addition, spindlactone (SPL) and Specific and Non-genetic IAP-dependent Protein Eraser (SNIPER) (TACC3) have been developed as TACC3 inhibitors [22, 34]. SPL suppresses the extension of the microtubule from the centrosome and causes mitotic defects in tumor cells by inhibiting TACC3, whereas SNIPER (TACC3) selectively induces apoptosis in tumor cells expressing increased levels of TACC3 by polyubiquitylation and proteasomal degradation. These studies indicate that TACC3 may represent a novel, promising therapeutic target, although the potential must be tested either in animal models or in proper clinical trials. In this study, we provide no evidence that these approaches will be successful.

In conclusion, we demonstrated for the first time that high TACC3 expression is correlated with poor prognosis in patients with osteosarcoma. Further studies about mutation or an inactive form of TACC3 may reveal how TACC3 is abnormally expressed in osteosarcoma. If substantiated in a larger study, the observations from this pilot study might provide the rationale to use TACC3 as a potential therapeutic target.

Back to Top | Article Outline

Acknowledgments

We thank Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, Kaoruko Nagatomo, Marina Sakata, and Kensaku Sato for their technical support.

Back to Top | Article Outline

References

1. Akobeng AK. Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr. 2007;96:644–647.
2. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY, USA: Springer; 2017.
3. Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E, Forni C, Briccoli A. High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008;98:415–420.
4. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–1715.
5. Gergely F. Centrosomal TACCtics. Bioessays. 2002;24:915–925.
6. Ha GH, Kim JL, Breuer EK. Transforming acidic coiled-coil proteins (TACCs) in human cancer. Cancer Lett. 2013;336:24–33.
7. Ha GH, Kim JL, Petersson A, Oh S, Denning MF, Patel T, Breuer EK. TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition. Oncogene. 2015;34:1667–1678.
8. Ha GH, Park JS, Breuer EK. TACC3 promotes epithelial-mesenchymal transition (EMT) through the activation of PI3K/Akt and ERK signaling pathways. Cancer Lett. 2013;332:63–73.
9. Harrison MR, Holen KD, Liu G. Beyond taxanes: a review of novel agents that target mitotic tubulin and microtubules, kinases, and kinesins. Clin Adv Hematol Oncol. 2009;7:54–64.
10. Harting MT, Blakely ML. Management of osteosarcoma pulmonary metastases. Semin Pediatr Surg. 2006;15:25–29.
11. Huang ZL, Lin ZR, Xiao YR, Cao X, Zhu LC, Zeng MS, Zhong Q, Wen ZS. High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis. Oncotarget. 2015;6:6850–6861.
12. Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: current treatment and a collaborative pathway to success. J Clin Oncol. 2015;33:3029–3035.
13. Iwamoto Y, Tanaka K, Isu K, Kawai A, Tatezaki S, Ishii T, Kushida K, Beppu Y, Usui M, Tateishi A, Furuse K, Minamizaki T, Kawaguchi N, Yamawaki S. Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J. J Orthop Sci. 2009;14:397–404.
14. Jiang L, Tao C, He A. Prognostic significance of p53 expression in malignant bone tumors: a meta-analysis. Tumour Biol. 2013;34:1037–1043.
15. Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY. Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in non-small cell lung cancer. Pathol Int. 2006;56:503–509.
16. Kim MS, Lee SY, Cho WH, Song WS, Koh JS, Lee JA, Yoo JY, Shin DS, Jeon DG. An examination of the efficacy of the 8 cm maximal tumor diameter cutoff for the subdivision of AJCC stage II osteosarcoma patients. J Surg Oncol. 2008;98:427–431.
17. Kubo T, Shimose S, Fujimori J, Furuta T, Arihiro K, Ochi M. Does expression of glucose transporter protein-1 relate to prognosis and angiogenesis in osteosarcoma? Clin Orthop Relat Res. 2015;473:305–310.
18. LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J, Bowman D, Galvin K, Ecsedy JA. Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res. 2007;67:5362–5370.
19. Matsuda K, Miyoshi H, Hiraoka K, Yokoyama S, Haraguchi T, Hashiguchi T, Hamada T, Shiba N, Ohshima K. Clinicopathological and prognostic value of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in soft tissue sarcomas. PLoS One. 2017;12:e0188096.
20. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115:1531–1543.
21. Nahm JH, Kim H, Lee H, Cho JY, Choi YR, Yoon YS, Han HS, Park YN. Transforming acidic coiled-coil-containing protein 3 (TACC3) overexpression in hepatocellular carcinomas is associated with ‘stemness’ and epithelial-mesenchymal transition-related marker expression and a poor prognosis. Tumour Biol. 2016;37:393–403.
22. Ohoka N, Nagai K, Hattori T, Okuhira K, Shibata N, Cho N, Naito M. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway. Cell Death Dis. 2014;5:e1513.
23. Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, Sexl V, Snyder L, Rehg J, Ihle JN. The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J. 2002;21:653–664.
24. Raff JW. Centrosomes and cancer: lessons from a TACC. Trends Cell Biol. 2002;12:222–225.
25. Robl B, Pauli C, Botter SM, Bode-Lesniewska B, Fuchs B. Prognostic value of tumor suppressors in osteosarcoma before and after neoadjuvant chemotherapy. BMC Cancer. 2015;15:379.
26. Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982;49:1221–1230.
27. Rosenberg AE, Cleton-Jansen AM, de Pinieux G, Deyrup AT, Hauben E, Squire J. Conventional osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PC, Mertens F, eds. WHO Classification of Tumors of Soft Tissue and Bone. 4th ed. Lyon, France: International Agency for Research on Cancer; 2013:282–288.
28. Sadek CM, Pelto-Huikko M, Tujague M, Steffensen KR, Wennerholm M, Gustafsson JA. TACC3 expression is tightly regulated during early differentiation. Gene Expr Patterns. 2003;3:203–211.
29. Schmidt S, Schneider L, Essmann F, Cirstea IC, Kuck F, Kletke A, Janicke RU, Wiek C, Hanenberg H, Ahmadian MR, Schulze-Osthoff K, Nurnberg B, Piekorz RP. The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program. Oncogene. 2010;29:6184–6192.
30. Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Schulze-Osthoff K, Nurnberg B, Piekorz RP. TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. Oncogene. 2008;27:116–125.
31. Uchida A, Myoui A, Araki N, Yoshikawa H, Shinto Y, Ueda T. Neoadjuvant chemotherapy for pediatric osteosarcoma patients. Cancer. 1997;79:411–415.
32. Urakawa H, Nishida Y, Naruse T, Nakashima H, Ishiguro N. Cyclooxygenase-2 overexpression predicts poor survival in patients with high-grade extremity osteosarcoma: a pilot study. Clin Orthop Relat Res. 2009;467:2932–2938.
33. Uzan VR, Lengert A, Boldrini E, Penna V, Scapulatempo-Neto C, Scrideli CA, Filho AP, Cavalcante CE, de Oliveira CZ, Lopes LF, Vidal DO. High expression of HULC is associated with poor prognosis in osteosarcoma patients. PLoS One. 2016;11:e0156774.
34. Yao R, Kondoh Y, Natsume Y, Yamanaka H, Inoue M, Toki H, Takagi R, Shimizu T, Yamori T, Osada H, Noda T. A small compound targeting TACC3 revealed its different spatiotemporal contributions for spindle assembly in cancer cells. Oncogene. 2014;33:4242–4252.
35. Yao R, Natsume Y, Saiki Y, Shioya H, Takeuchi K, Yamori T, Toki H, Aoki I, Saga T, Noda T. Disruption of Tacc3 function leads to in vivo tumor regression. Oncogene. 2012;31:135–148.
36. Yun M, Rong J, Lin ZR, He YL, Zhang JX, Peng ZW, Tang LQ, Zeng MS, Zhong Q, Ye S. High expression of transforming acidic coiled coil-containing protein 3 strongly correlates with aggressive characteristics and poor prognosis of gastric cancer. Oncol Rep. 2015;34:1397–1405.
37. Zhou DS, Wang HB, Zhou ZG, Zhang YJ, Zhong Q, Xu L, Huang YH, Yeung SC, Chen MS, Zeng MS. TACC3 promotes stemness and is a potential therapeutic target in hepatocellular carcinoma. Oncotarget. 2015;6:24163–24177.
© 2018 Lippincott Williams & Wilkins LWW