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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 promotes cell invasion and gastric cancer metastasis(A) Wound-healing assay showed that over-expression of ZIPK promoted cell migration. Silencing ZIPK inhibited cell migration (Scale bars: 100 μm). Representative images were taken at 0 h, 48 h and 72 h after scratching. (B) Transwell assay indicated that over-expression of ZIPK promoted cell migration and invasion. Inversely, ZIPK ablation repressed cell migration and invasion (Scale bars: 100 μm). (C) The effects of ZIPK on tumor metastasis in vivo were evaluated by tail vein injections of cells in nude mice. Representative images of lungs derived from nude mice injected with ZIPK- or empty vector-transfected BGC823 cells were shown in the left panel. Number of visible surface metastatic lesions was indicated in the right panel (*indicates P < 0.05, independent Student's t-test). (D) Lung metastases in the mice were confirmed by H&E staining (Scale bars: 100 μm).
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Figure 2: ZIPK promotes cell invasion and gastric cancer metastasis(A) Wound-healing assay showed that over-expression of ZIPK promoted cell migration. Silencing ZIPK inhibited cell migration (Scale bars: 100 μm). Representative images were taken at 0 h, 48 h and 72 h after scratching. (B) Transwell assay indicated that over-expression of ZIPK promoted cell migration and invasion. Inversely, ZIPK ablation repressed cell migration and invasion (Scale bars: 100 μm). (C) The effects of ZIPK on tumor metastasis in vivo were evaluated by tail vein injections of cells in nude mice. Representative images of lungs derived from nude mice injected with ZIPK- or empty vector-transfected BGC823 cells were shown in the left panel. Number of visible surface metastatic lesions was indicated in the right panel (*indicates P < 0.05, independent Student's t-test). (D) Lung metastases in the mice were confirmed by H&E staining (Scale bars: 100 μm).

Mentions: After confirming the tumorigenic ability of ZIPK, we investigated the roles of ZIPK in cell migration, invasion and tumor metastasis. Wound healing assay showed that ZIPK-transfected cells obtained quicker closure of the scratched “wound” and silencing ZIPK resulted in a significant delay of scratch area closure (Figure 2A). In addition, we further measured cell migration and invasion using Transwell assays in ZIPK-transfected, ZIPK-silenced and their respective control cells. ZIPK overexpression significantly increased cell migration and invasiveness in BGC-823 cell line. Knockdown of ZIPK repressed cell migration and invasion in SGC-7901 and SNU-1 cells (P < 0.001; Figure 2B). To evaluate the in vivo effects of ZIPK on tumor metastasis, two groups of 5 mice each were injected intravenously in the tail vein with ZIPK-transfected cells or Vec-BGC823, respectively. After 8 weeks, the mice were sacrificed, and the metastatic nodules at the lung surfaces were counted. A significantly larger number of metastatic nodules were induced at the surface of the lungs of mice injected with the ZIPK-transfected cells than those with the Vec-BGC823 cells (P < 0.001, Figure 2C). Hematoxylin and eosin (H&E) staining confirmed that the nodules on the surfaces of mice lungs were metastatic tumors. Histological analyses further revealed that ZIPK promoted metastasis of BGC-823 cell line (Figure 2D).


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 promotes cell invasion and gastric cancer metastasis(A) Wound-healing assay showed that over-expression of ZIPK promoted cell migration. Silencing ZIPK inhibited cell migration (Scale bars: 100 μm). Representative images were taken at 0 h, 48 h and 72 h after scratching. (B) Transwell assay indicated that over-expression of ZIPK promoted cell migration and invasion. Inversely, ZIPK ablation repressed cell migration and invasion (Scale bars: 100 μm). (C) The effects of ZIPK on tumor metastasis in vivo were evaluated by tail vein injections of cells in nude mice. Representative images of lungs derived from nude mice injected with ZIPK- or empty vector-transfected BGC823 cells were shown in the left panel. Number of visible surface metastatic lesions was indicated in the right panel (*indicates P < 0.05, independent Student's t-test). (D) Lung metastases in the mice were confirmed by H&E staining (Scale bars: 100 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: ZIPK promotes cell invasion and gastric cancer metastasis(A) Wound-healing assay showed that over-expression of ZIPK promoted cell migration. Silencing ZIPK inhibited cell migration (Scale bars: 100 μm). Representative images were taken at 0 h, 48 h and 72 h after scratching. (B) Transwell assay indicated that over-expression of ZIPK promoted cell migration and invasion. Inversely, ZIPK ablation repressed cell migration and invasion (Scale bars: 100 μm). (C) The effects of ZIPK on tumor metastasis in vivo were evaluated by tail vein injections of cells in nude mice. Representative images of lungs derived from nude mice injected with ZIPK- or empty vector-transfected BGC823 cells were shown in the left panel. Number of visible surface metastatic lesions was indicated in the right panel (*indicates P < 0.05, independent Student's t-test). (D) Lung metastases in the mice were confirmed by H&E staining (Scale bars: 100 μm).
Mentions: After confirming the tumorigenic ability of ZIPK, we investigated the roles of ZIPK in cell migration, invasion and tumor metastasis. Wound healing assay showed that ZIPK-transfected cells obtained quicker closure of the scratched “wound” and silencing ZIPK resulted in a significant delay of scratch area closure (Figure 2A). In addition, we further measured cell migration and invasion using Transwell assays in ZIPK-transfected, ZIPK-silenced and their respective control cells. ZIPK overexpression significantly increased cell migration and invasiveness in BGC-823 cell line. Knockdown of ZIPK repressed cell migration and invasion in SGC-7901 and SNU-1 cells (P < 0.001; Figure 2B). To evaluate the in vivo effects of ZIPK on tumor metastasis, two groups of 5 mice each were injected intravenously in the tail vein with ZIPK-transfected cells or Vec-BGC823, respectively. After 8 weeks, the mice were sacrificed, and the metastatic nodules at the lung surfaces were counted. A significantly larger number of metastatic nodules were induced at the surface of the lungs of mice injected with the ZIPK-transfected cells than those with the Vec-BGC823 cells (P < 0.001, Figure 2C). Hematoxylin and eosin (H&E) staining confirmed that the nodules on the surfaces of mice lungs were metastatic tumors. Histological analyses further revealed that ZIPK promoted metastasis of BGC-823 cell line (Figure 2D).

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