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

Journal of Experimental & Clinical Cancer Research

Huamei Tang²  Zhihai Peng¹  Yang Yu¹  Yu Zhang²  Shaofei Ma²  Senlin Zhao¹  Jian Chen¹  Jingtao Wang¹  Yingming Xue¹  Huijun Lu²  Su Lu²  Feifei Cui¹  Meng Zhang² 

[1] Departments of General Surgery, Shanghai Jiaotong University Affiiated First People’s Hospital, Shanghai 200080, People’s Republic of China;Departments of Pathology, Shanghai Jiaotong University Affiiated First People’s Hospital, Shanghai 200080, People’s Republic of China

关键词: Proliferation;    Prognosis;    Immunohistochemistry;    Dppa4;    Colon cancer;   

Others  :  1220678
DOI  :  10.1186/s13046-015-0176-z

 received in 2015-02-18, accepted in 2015-05-27,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Zhang et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 2001, 414(6859):105-11.
• [2]Abdul Khalek FJ, Gallicano GI, Mishra L. Colon cancer stem cells. Gastrointest Cancer Res. 2010 Nov-Dec;(Suppl 1):S16–23.
• [3]Rosen JM, Jordan CT: The increasing complexity of the cancer stem cell paradigm. Science (New York, NY) 2009, 324(5935):1670-3.
• [4]Visvader JE, Lindeman GJ: Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012, 10(6):717-28.
• [5]Yin ZQ, Liu JJ, Xu YC, Yu J, Ding GH, Yang F, et al.: A 41-gene signature derived from breast cancer stem cells as a predictor of survival. J Exp Clin Cancer Res : CR 2014, 33:49. BioMed Central Full Text
• [6]Al-Hajj M, Clarke MF: Self-renewal and solid tumor stem cells. Oncogene 2004, 23(43):7274-82.
• [7]Clarke MF, Fuller M: Stem cells and cancer: two faces of eve. Cell 2006, 124(6):1111-5.
• [8]Pardal R, Clarke MF, Morrison SJ: Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003, 3(12):895-902.
• [9]Amini S, Fathi F, Mobalegi J, Sofimajidpour H, Ghadimi T: The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anat Cell Biol 2014, 47(1):1-11.
• [10]Li L, Yu H, Wang X, Zeng J, Li D, Lu J, et al.: Expression of seven stem-cell-associated markers in human airway biopsy specimens obtained via fiberoptic bronchoscopy. J Exp Clin Cancer Res : CR 2013, 32:28. BioMed Central Full Text
• [11]Chakravarthy H, Boer B, Desler M, Mallanna SK, McKeithan TW, Rizzino A: Identification of DPPA4 and other genes as putative Sox2:Oct-3/4 target genes using a combination of in silico analysis and transcription-based assays. J Cell Physiol 2008, 216(3):651-62.
• [12]Masaki H, Nishida T, Sakasai R, Teraoka H: DPPA4 modulates chromatin structure via association with DNA and core histone H3 in mouse embryonic stem cells. Genes Cells 2010, 15(4):327-37.
• [13]Tung PY, Varlakhanova NV, Knoepfler PS: Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes. Stem Cells (Dayton, Ohio) 2013, 31(11):2330-42.
• [14]Yan DW, Li DW, Yang YX, Xia J, Wang XL, Zhou CZ, et al.: Ubiquitin D is correlated with colon cancer progression and predicts recurrence for stage II-III disease after curative surgery. Br J Cancer 2010, 103(7):961-9.
• [15]Dean SJ, Perks CM, Holly JM, Bhoo-Pathy N, Looi LM, Mohammed NA, et al.: Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. Am J Clin Pathol 2014, 141(3):323-33.
• [16]Zhang S, Yang YL, Wang Y, You B, Dai Y, Chan G, et al.: CK2 inverted question mark, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells. J Exp Clin Cancer Res : CR 2014, 33(1):93.
• [17]Pathologists’ guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Breast Care (Basel, Switz). 2010;5(3):185–7. doi:000315039.
• [18]Ezeh UI, Turek PJ, Reijo RA, Clark AT: Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 2005, 104(10):2255-65.
• [19]Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J, Klein B: Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun 2009, 383(2):157-62.
• [20]Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, et al.: Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells (Dayton, Ohio) 2009, 27(5):993-1005.
• [21]Du J, Chen T, Zou X, Xiong B, Lu G: Dppa2 knockdown-induced differentiation and repressed proliferation of mouse embryonic stem cells. J Biochem 2010, 147(2):265-71.
• [22]Maldonado-Saldivia J, van den Bergen J, Krouskos M, Gilchrist M, Lee C, Li R, et al.: Dppa2 and Dppa4 are closely linked SAP motif genes restricted to pluripotent cells and the germ line. Stem Cells (Dayton, Ohio) 2007, 25(1):19-28.
• [23]Aravind L, Koonin EV: SAP—a putative DNA-binding motif involved in chromosomal organization. Trends Biochem Sci 2000, 25(3):112-4.
• [24]Masaki H, Nishida T, Kitajima S, Asahina K, Teraoka H: Developmental pluripotency-associated 4 (DPPA4) localized in active chromatin inhibits mouse embryonic stem cell differentiation into a primitive ectoderm lineage. J Biol Chem 2007, 282(45):33034-42.