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Int J Mol Sci
2014 Oct 09;1510:18148-61. doi: 10.3390/ijms151018148.
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TPX2 is a prognostic marker and contributes to growth and metastasis of human hepatocellular carcinoma.
Huang Y
,
Guo W
,
Kan H
.
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Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression level of TPX2 was obviously higher in hepatocellular carcinoma (HCC) tissues than in matched nontumor tissues. Elevated expressions of TPX2 mRNA were observed in all HCC cell lines (HepG2, Hep3B, SMMC-7721, Bel-7402 and Huh7) as compared with that in a non-transformed hepatic cell line (LO2). Clinical analysis indicated that the positive expression of TPX2 was significantly correlated with venous infiltration, high Edmondson-Steiner grading and advanced TNM tumor stage in HCC. Furthermore, TPX2 was a novel prognostic marker for predicting 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. In vitro studies found that TPX2 knockdown significantly inhibited cell proliferation and viability in both Hep3B and HepG2 cells. Moreover, TPX2 knockdown obviously slowed down tumor growth in a nude mouse xenograft model. Otherwise, TPX2 knockdown prominently suppressed HCC cell invasion and migration. In conclusion, these results indicate that TPX2 may serve as a prognostic marker and promotes tumorigenesis and metastasis of HCC.
Figure 1. The expression levels of TPX2 in hepatocellular carcinoma (HCC) tissues and cells. Comparing differences in the expression levels of TPX2 between (A) and (B) HCC (T) and matched nontumor tissues (NT) (n = 20), and (C) HCC cell lines and the immortalized hepatic cell line LO2 (n = 6). Values are depicted as Mean ± SEM; *
p < 0.05 by t test.
Figure 2. The immunostaining of TPX2 and its prognostic significance in HCC specimens. (A) Immunohistochemical staining of TPX2 in HCC. TPX2 was localized within the nuclei. Elevated expression of TPX2 (the arrows) in the tumor cells of HCC tissue (II, III, and IV) compared to normal tumor-adjacent tissues with negative staining (I) (scale bar: 100 μm); (B) The overall survival (OS) and (C) disease-free survival rates (DFS) were estimated by the Kaplan-Meier method. Both the OS rate and DFS rate of patients with TPX2 positive primary tumor were significantly lower than that of patients with TPX2 negative primary tumor (log-rank test, p < 0.05).
Figure 3. TPX2 knockdown inhibits cell proliferation and viability in HCC. (A) Hep3B and HepG2 cells that were transfected with non-targeting (NT) shRNA and TPX2 shRNA, respectively, were subjected to WB for TPX2. n = 6; *
p < 0.05 by t test; (B) Cell proliferation as measured by BrdU incorporation was inhibited by TPX2 knockdown in Hep3B and HepG2 cells. *
p < 0.05 by t test; n = 3 repeats with similar results; (C) As assessed by MTT assays, TPX2 knockdown was found to reduce the viability of Hep3B and HepG2 cells. *
p < 0.05 by two-way ANOVA; n = 3 repeats with similar results. Values are depicted as Mean ± SEM.
Figure 4. TPX2 knockdown suppresses tumor growth in mice. (A) Hep3B cells that were transfected with NT shRNA or TPX2 shRNA were implanted into nude mice through subcutaneous injection. Tumor growth curves indicated that TPX2 knockdown Hep3B cells (n = 6) exhibited a greater tumor-inhibiting effect compared with control cells (n = 6). Scale bar: 100 μm; *
p < 0.05 by two-way ANOVA; (B) Tumor nodules were subjected to immunohistochemical staining for Ki-67 and quantitative analysis. Representative immunostaining of Ki-67 (the arrows) revealed that TPX2 knockdown significantly reduced the number of Ki-67 positive cells. Scale bar: 100 μm; n = 6; *
p < 0.05 by t test.
Figure 5. TPX2 knockdown inhibits HCC cell migration and invasion. Cell migration as measured by Boyden chamber assays was inhibited by TPX2 knockdown in Hep3B and HepG2 cells as compared with control cells. TPX2 down-regulating Hep3B and HepG2 cells conferred a less number of invaded cells as compared with control cells. n = 6 repeats with similar results; *
p < 0.05 by t test. Values are depicted as Mean ± SEM.
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