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Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients.

Li J, Deng Z, Wang Z, Wang D, Zhang L, Su Q, Lai Y, Li B, Luo Z, Chen X, Chen Y, Huang X, Ma J, Wang W, Bi J, Guan X - Oncotarget (2015)

Bottom Line: Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family.Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion.Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.

ABSTRACT
Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of β-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IκB/NF-κB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis.

No MeSH data available.


Related in: MedlinePlus

ZIPK induces epithelial-mesenchymal transition(A) Effect of ZIPK over-expression on cell morphology evaluated by phase-contrast microscopy (Scale bars: 100 μm). (B) Expression of epithelial cell marker (E-cadherin), mesenchymal cell markers (vimentin, fironectin and N-cadherin) and β-catenin were examined by Western blot analysis in ZIPK-overexpressed, ZIPK-silenced and their respective control cells. GAPDH was used as a loading control. Intensities of bands were analyzed by the Macintosh densitometry program Image J (NIH, Bethesda, MD). (C) Relative expressions of E-cadherin, N-cadherin, vimentin, fibronectin, β-catenin were detected by qPCR in ZIPK-overexpressed, ZIPK-silenced and their respective control cells.
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Figure 3: ZIPK induces epithelial-mesenchymal transition(A) Effect of ZIPK over-expression on cell morphology evaluated by phase-contrast microscopy (Scale bars: 100 μm). (B) Expression of epithelial cell marker (E-cadherin), mesenchymal cell markers (vimentin, fironectin and N-cadherin) and β-catenin were examined by Western blot analysis in ZIPK-overexpressed, ZIPK-silenced and their respective control cells. GAPDH was used as a loading control. Intensities of bands were analyzed by the Macintosh densitometry program Image J (NIH, Bethesda, MD). (C) Relative expressions of E-cadherin, N-cadherin, vimentin, fibronectin, β-catenin were detected by qPCR in ZIPK-overexpressed, ZIPK-silenced and their respective control cells.

Mentions: As shown in Figure 3A, overexpression of ZIPK led to altered morphological characteristics of epithelial-mesenchymal transition (EMT), identified by a scattered distribution of cells and spindle or star-like morphology of the cells in culture. Since the in vitro and in vivo experiments showed that ZIPK could play a pivotal role in gastric cancer cell metastasis, we next asked whether ZIPK affect on cell biological programs that initiate metastasis cascades. EMT has been recognized as a critical event in tumor metastasis. To validate whether ZIPK enhances gastric cancer metastasis via inducing EMT, the expression levels of EMT markers were detected by Western blot and qRT-PCR in ZIPK-transfected, ZIPK-silenced and their respective control cells. We found that the epithelial marker, E-cadherin was dramatically down-regulated in the ZIPK-transfected cells, but mesenchymal markers such as vimentin and fibronectin were strongly up-regulated in ZIPK transfectcted BGC-823 cells. Moreover, overexpression of ZIPK increased β-catenin and its nuclear translocation. As expected, opposite expression profiles of these proteins were detected in ZIPK-silenced cells (Figure 3B, 3C). Increased nuclear accumulation of β-catenin is a known transcription factor that regulates the activity of TCF/LEF family to facilitate EMT and metastasis [13]. Collectively, these data suggest that ZIPK might be a positive mediator of EMT and metastasis in gastric cancer cells.


Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients.

Li J, Deng Z, Wang Z, Wang D, Zhang L, Su Q, Lai Y, Li B, Luo Z, Chen X, Chen Y, Huang X, Ma J, Wang W, Bi J, Guan X - Oncotarget (2015)

ZIPK induces epithelial-mesenchymal transition(A) Effect of ZIPK over-expression on cell morphology evaluated by phase-contrast microscopy (Scale bars: 100 μm). (B) Expression of epithelial cell marker (E-cadherin), mesenchymal cell markers (vimentin, fironectin and N-cadherin) and β-catenin were examined by Western blot analysis in ZIPK-overexpressed, ZIPK-silenced and their respective control cells. GAPDH was used as a loading control. Intensities of bands were analyzed by the Macintosh densitometry program Image J (NIH, Bethesda, MD). (C) Relative expressions of E-cadherin, N-cadherin, vimentin, fibronectin, β-catenin were detected by qPCR in ZIPK-overexpressed, ZIPK-silenced and their respective control cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480755&req=5

Figure 3: ZIPK induces epithelial-mesenchymal transition(A) Effect of ZIPK over-expression on cell morphology evaluated by phase-contrast microscopy (Scale bars: 100 μm). (B) Expression of epithelial cell marker (E-cadherin), mesenchymal cell markers (vimentin, fironectin and N-cadherin) and β-catenin were examined by Western blot analysis in ZIPK-overexpressed, ZIPK-silenced and their respective control cells. GAPDH was used as a loading control. Intensities of bands were analyzed by the Macintosh densitometry program Image J (NIH, Bethesda, MD). (C) Relative expressions of E-cadherin, N-cadherin, vimentin, fibronectin, β-catenin were detected by qPCR in ZIPK-overexpressed, ZIPK-silenced and their respective control cells.
Mentions: As shown in Figure 3A, overexpression of ZIPK led to altered morphological characteristics of epithelial-mesenchymal transition (EMT), identified by a scattered distribution of cells and spindle or star-like morphology of the cells in culture. Since the in vitro and in vivo experiments showed that ZIPK could play a pivotal role in gastric cancer cell metastasis, we next asked whether ZIPK affect on cell biological programs that initiate metastasis cascades. EMT has been recognized as a critical event in tumor metastasis. To validate whether ZIPK enhances gastric cancer metastasis via inducing EMT, the expression levels of EMT markers were detected by Western blot and qRT-PCR in ZIPK-transfected, ZIPK-silenced and their respective control cells. We found that the epithelial marker, E-cadherin was dramatically down-regulated in the ZIPK-transfected cells, but mesenchymal markers such as vimentin and fibronectin were strongly up-regulated in ZIPK transfectcted BGC-823 cells. Moreover, overexpression of ZIPK increased β-catenin and its nuclear translocation. As expected, opposite expression profiles of these proteins were detected in ZIPK-silenced cells (Figure 3B, 3C). Increased nuclear accumulation of β-catenin is a known transcription factor that regulates the activity of TCF/LEF family to facilitate EMT and metastasis [13]. Collectively, these data suggest that ZIPK might be a positive mediator of EMT and metastasis in gastric cancer cells.

Bottom Line: Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family.Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion.Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.

ABSTRACT
Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of β-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IκB/NF-κB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis.

No MeSH data available.


Related in: MedlinePlus