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. 2015 Jun 11;34(1):60.
doi: 10.1186/s13046-015-0176-z.

Developmental pluripotency-associated 4: a novel predictor for prognosis and a potential therapeutic target for colon cancer

Meng Zhang  1 , Feifei Cui  2 , Su Lu  3 , Huijun Lu  4 , Yingming Xue  5 , Jingtao Wang  6 , Jian Chen  7 , Senlin Zhao  8 , Shaofei Ma  9 , Yu Zhang  10 , Yang Yu  11 , Zhihai Peng  12 , Huamei Tang  13
Affiliations

Developmental pluripotency-associated 4: a novel predictor for prognosis and a potential therapeutic target for colon cancer

Meng Zhang et al. J Exp Clin Cancer Res. .

Abstract

Backgrounds: Developmental pluripotency-associated 4 (Dppa4) gene plays an important role in self-renewal and pluripotency sustainability in embryonic stem cells. It is re-expressed in several malignant tumors and is identified as a new pluripotency-related oncogene. The present study investigates the expression and clinical significance of Dppa4 in colon cancer.

Methods: Real-time polymerase chain reaction and Western blotting were used to evaluate Dppa4 mRNA and protein expression in 39 pairs of fresh-frozzen colon cancer samples, which were compared with adjacent normal mucosa. The Dppa4 protein was evaluated by immunohistochemical techniques using colon tissue microarrays (TMA). The sample included 185 cancer specimens and corresponding normal colorectal mucosa. The effect of Dppa4 knockdown on colorectal cancer cell proliferation was investigated using Cell Counting Kit-8 (CCK8) assays and colony-formation assays.

Results: Both the mRNA and protein level expression of Dppa4 gene was found to be upregulated in colon cancer tissues. Furthermore, the upregulated expression of Dppa4 was significantly correlated with the results of American Joint Committee on Cancer (AJCC) stage (P = 0.01), invasion depth (P = 0.028), nodal involvement (P = 0.012), distant metastasis (P = 0.003), and differentiation (P = 0.002). Dppa4 was also shown to be an independent prognostic indicator of disease-free survival (HR 6.118, 95 % CI 3.004-12.462) and overall survival (HR 6.348, 95 % CI 2.875-14.014) for patients with colon cancer. Knockdown of Dppa4 expression inhibited the proliferation of colorectal cancer cell lines through G1/S transition regulation.

Conclusion: The results indicate that Dppa4 might play an important role in colon cancer progression and function as a novel prognostic indicator and a potential therapeutic target.

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Figures

Fig. 1
Fig. 1
Analysis of Dppa4 expression in human colon cancer tissues. a Dppa4 mRNA levels in 39 primary tumor tissues and paired normal tissues detected by real-time PCR. Dppa4 mRNA level was normalized using GAPDH expression. A logarithmic scale of 2-ΔΔCT was used to represent the fold-change. b Western blot analysis was performed to access Dppa4 protein levels in 8 representative cases of colon cancer samples (T) and adjacent noncancerous tissues (N). c Dppa4 protein is higher in tumor tissues than in paired adjacent normal mucosa
Fig. 2
Fig. 2
Immunohistochemical staining of Dppa4 expression in tissue microarrays. a Negative-Dppa4 expression in normal colonic epithelium and (b) Diffuse, intense Dppa4 staining in moderately and poorly-differentiated colon tumors; (c) colon cancer lymph node metastasis. Original magnification × 200 (×50 for inserts). (d) Dppa4 expression in 185 cases of paired normal colon tissue, primary colon cancer and 63 cases of lymph node metastasis (LNM). Dppa4 expression was significantly higher in LNM than in primary colon cancer and normal colon tissue. (P < 0.001)
Fig. 3
Fig. 3
Kaplan-Meier survival analysis of 5-year OS and DFS in 177 patients with colon cancer. Dppa4 expression was dramatically correlated with poor OS and DFS
Fig. 4
Fig. 4
Dppa4 expression in cell lines and its knockdown inhibits cancer cell proliferation. a Dppa4 protein levels and (b) mRNA levels in 8 colorectal cancer cell lines. c Western blot analysis, and (d) real-time PCR analysis of Dppa4 expression in stable knockdown CaCo2 and HCT8 cell lines. e Effects of Dppa4 knockdown on proliferation was evaluated by Cell Counting Kit-8 assays and (f) plate colony formation assays. g Real-time PCR analysis of proliferation related genes and G1/S transition genes. (* P < 0.05, *** P < 0.01)
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