Research on the relationship between the novel chemokine receptor CXCR7 and pancreatic carcinoma development and progression_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Xin , LIU Zhen , SUN Shaolong , WU Xin , MENG Xiangpeng , YAO Wei ,  WANG Baosheng

Department of Pancreatic and Endocrine Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, P.R.China;

Corresponding author：

WANG Baosheng, Email: xixicmu@126.com

Keywords：

pancreatic carcinoma; chemokine receptor CXCR7; proliferation; cell cycle; apoptosis; invasion

DOI：

10.7507/1007-9424.201702043

Video：

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Objective To investigate the role of chemokine receptor CXCR7 in the development and progression of pancreatic carcinoma. Methods The short hairpin RNA (shRNA) targeting CXCR7 was designed and delivered into AsPC-1 pancreatic carcinoma cells to knock down CXCR7 expression. The cell proliferation, cell cycle, and apoptosis after CXCR7 knockdown was determined by MTT and flow cytometry, respectively. The invasive ability of pancreatic carcinoma cells was evaluated by using the Transwell system. Results Compared with the blank control group (BC group), transfection of AsPC-1 cells with CXCR7-shRNA resulted in a significantly decreased expression of CXCR7 at both mRNA and protein levels (P<0.05), and the ability of proliferation and invasion significantly decreased (P<0.05). Knockdown of CXCR7 also significantly increase apoptosis (P<0.05), induce cell cycle arrest at G₀/G₁ phase (P<0.05). Conclusions Taken together, the present study showes that the knockdown of CXCR7 expression may play an important role in pancreatic carcinoma development, invasion, and metastasis, CXCR7 may be a potential therapeutic target for the treatment of pancreatic carcinoma.

Citation： ZHANG Xin, LIU Zhen, SUN Shaolong, WU Xin, MENG Xiangpeng, YAO Wei, WANG Baosheng. Research on the relationship between the novel chemokine receptor CXCR7 and pancreatic carcinoma development and progression. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(8): 940-945. doi: 10.7507/1007-9424.201702043 Copy

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2.	Kakinuma T, Hwang ST. Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol, 2006, 79(4): 639-651.
3.	Bagri A, Gurney T, He X, et al. The chemokine SDF-1 regulates migration of dentate granule cells. Development, 2002, 129(18): 4249-4260.
4.	Lazarini F, Tham TN, Casanova P, et al. Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia, 2003, 42(2): 139-148.
5.	Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006, 203(9): 2201-2213.
6.	Boldajipour B, Mahabaleshwar H, Kardash E, et al. Control of chemokine-guided cell migration by ligand sequestration. Cell, 2008, 132(3): 463-473.
7.	Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage Ⅰ nonsmall cell lung cancer. Cancer, 2009, 115(11): 2580-2593.
8.	Hattermann K, Held-Feindt J, Lucius R, et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res, 2010, 70(8): 3299-3308.
9.	Zheng K, Li HY, Su XL, et al. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells. J Exp Clin Cancer Res, 2010, 29: 31.
10.	Singh RK, Lokeshwar BL. The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res, 2011, 71(9): 3268-3277.
11.	Liu Z, Teng XY, Meng XP, et al. Expression of stromal cell-derived factor 1 and CXCR7 ligand receptor system in pancreatic adenocarcinoma. World J Surg Oncol, 2014, 12: 348.
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13.	Araki S, Omori Y, Lyn D, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res, 2007, 67(14): 6854-6862.
14.	Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature, 1996, 382(6594): 833-835.
15.	Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor associated vasculature. Proc Natl Acad Sci USA, 2007, 104(40): 15735-15740.
16.	Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem, 2008, 283(7): 4283-4294.
17.	Maréchal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer, 2009, 100(9): 1444-1451.
18.	Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol, 2012, 84(2): 204-214.
19.	Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impactof CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol, 2011, 104(2): 140-145.
20.	Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys, 2014, 89(4): 830-838.
21.	Thelen M, Thelen S. CXCR7, CXCR4 and CXCL12: an eccentric trio? J Neuroimmunol, 2008, 198(1-2): 9-13.
22.	Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer, 2008, 99(9): 1493-1501.
23.	Xue TC, Chen RX, Han D, et al. Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med, 2012, 3(1): 117-123.
24.	Zabel BA, Miao Z, Lai NL, et al. CXCR7 protein expression correlates with elevated mmp-3 secretion in breast cancer cells. Oncol Lett, 2010, 1(5): 845-847.
25.	Roy I, Zimmerman NP, Mackinnon AC, et al. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One, 2014, 9(3): e90400.
26.	Ahmad N, Feyes DK, Agarwal R, et al. Photodynamic therapy results in induction of WAF1/CIP1/P21 leading to cell cycle arrest and apoptosis. Proc Natl Acad Sci USA, 1998, 95(12): 6977-6982.
27.	Liu Z, Yang L, Teng X, et al. The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma. J Surg Res, 2014, 191(2): 379-388.

1. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature, 2001, 410(6824): 50-56.
2. Kakinuma T, Hwang ST. Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol, 2006, 79(4): 639-651.
3. Bagri A, Gurney T, He X, et al. The chemokine SDF-1 regulates migration of dentate granule cells. Development, 2002, 129(18): 4249-4260.
4. Lazarini F, Tham TN, Casanova P, et al. Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia, 2003, 42(2): 139-148.
5. Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006, 203(9): 2201-2213.
6. Boldajipour B, Mahabaleshwar H, Kardash E, et al. Control of chemokine-guided cell migration by ligand sequestration. Cell, 2008, 132(3): 463-473.
7. Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage Ⅰ nonsmall cell lung cancer. Cancer, 2009, 115(11): 2580-2593.
8. Hattermann K, Held-Feindt J, Lucius R, et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res, 2010, 70(8): 3299-3308.
9. Zheng K, Li HY, Su XL, et al. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells. J Exp Clin Cancer Res, 2010, 29: 31.
10. Singh RK, Lokeshwar BL. The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res, 2011, 71(9): 3268-3277.
11. Liu Z, Teng XY, Meng XP, et al. Expression of stromal cell-derived factor 1 and CXCR7 ligand receptor system in pancreatic adenocarcinoma. World J Surg Oncol, 2014, 12: 348.
12. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2^-△△Ct method. Methods, 2001, 25(4): 402-408.
13. Araki S, Omori Y, Lyn D, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res, 2007, 67(14): 6854-6862.
14. Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature, 1996, 382(6594): 833-835.
15. Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor associated vasculature. Proc Natl Acad Sci USA, 2007, 104(40): 15735-15740.
16. Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem, 2008, 283(7): 4283-4294.
17. Maréchal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer, 2009, 100(9): 1444-1451.
18. Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol, 2012, 84(2): 204-214.
19. Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impactof CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol, 2011, 104(2): 140-145.
20. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys, 2014, 89(4): 830-838.
21. Thelen M, Thelen S. CXCR7, CXCR4 and CXCL12: an eccentric trio? J Neuroimmunol, 2008, 198(1-2): 9-13.
22. Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer, 2008, 99(9): 1493-1501.
23. Xue TC, Chen RX, Han D, et al. Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med, 2012, 3(1): 117-123.
24. Zabel BA, Miao Z, Lai NL, et al. CXCR7 protein expression correlates with elevated mmp-3 secretion in breast cancer cells. Oncol Lett, 2010, 1(5): 845-847.
25. Roy I, Zimmerman NP, Mackinnon AC, et al. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One, 2014, 9(3): e90400.
26. Ahmad N, Feyes DK, Agarwal R, et al. Photodynamic therapy results in induction of WAF1/CIP1/P21 leading to cell cycle arrest and apoptosis. Proc Natl Acad Sci USA, 1998, 95(12): 6977-6982.
27. Liu Z, Yang L, Teng X, et al. The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma. J Surg Res, 2014, 191(2): 379-388.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research on the relationship between the novel chemokine receptor CXCR7 and pancreatic carcinoma development and progression

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