Silencing of HOXB9 suppresses cellular proliferation, angiogenesis, migration and invasion of prostate cancer cells

Springer Science and Business Media LLC - Tập 45 - Trang 1-12 - 2020
Hao Xu1, Shangjun Wu1, Xin Shen2, Ding Wu3, Zhenguo Qin4, Hao Wang4, Xiaogang Chen1, Xiaoqing Sun4
1Department of Urology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
2Department of Abdominal and Pelvic Medical Oncology II, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
3Department of Urology, Jinling Hospital, Nanjing Medical University, Nanjing, China
4Department of Urology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China

Tóm tắt

The Homeobox B9 (HOXB9) is a homeodomain-containing transcription factor that participates in the progression of various malignancies. Nevertheless, the functional role of HOXB9 in prostate cancer cells is largely unknown. Hence, we aimed to address the effect of HOXB9 on the progression of prostate cancer cells. Small interfering RNA (siRNA) against HOXB9 was used to downregulate HOXB9 expression in PC3 and DU145 cells. Western blotting was performed to detect the expression levels of HOXB9 and other related proteins. Cell proliferation was tested by the Cell Counting Kit-8 (CCK-8) and cell cycle and apoptosis were investigated by flow cytometry. Angiogenesis was examined using tube formation assays The Transwell assays were carried out to assess the migratory and invasive capacities of cells. Here, we found that HOXB9 knockdown significantly reduced cell proliferation via inducing cell cycle arrest at G1 phase. This treatment also reduced angiogenesis, migration and invasion abilities of PC3 and DU145 cells in vitro. We also found that HOXB9 knockdown inhibits the activation of the PI3K/AKT signaling pathway in prostate cancer cells. In conclusion, our findings revealed that HOXB9 promotes prostate cancer progression and might be a novel and effective therapeutic target for human prostate cancer.

Tài liệu tham khảo

Antonarakis ES and Eisenberger MA 2011 Expanding treatment options for metastatic prostate cancer. New Engl. J. Med. 364 2055–2058 Carmeliet P and Jain RK 2011 Molecular mechanisms and clinical applications of angiogenesis. Nature 473 298–307 Chen H and Sukumar S 2003 HOX genes: emerging stars in cancer. Cancer Biol. Ther. 2 524–525 Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J 2016 Cancer statistics in China 2015. CA Cancer J. Clin. 66 115–132 Chi KN, Bjartell A, Dearnaley D, Saad F, Schroder FH, Sternberg C, Tombal B and Visakorpi T 2009 Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur. Urol. 56 594–605 Chiba N, Ozawa Y, Hikita K, Okihara M, Sano T, Tomita K, Takano K and Kawachi S 2017 Increased expression of HOXB9 in hepatocellular carcinoma predicts poor overall survival but a beneficial response to sorafenib. Oncol. Rep. 37 2270–2276 Claesson-Welsh L and Welsh M 2013 VEGFA and tumour angiogenesis. J. Intern. Med. 273 114–127 De Pinieux G, Legrier ME, Poirson-Bichat F, Courty Y, Bras-Goncalves R, Dutrillaux AM, Nemati F, Oudard S, Lidereau R, Broqua P, Junien JL, Dutrillaux B and Poupon MF 2001 Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach. Am. J. Pathol. 159 753–764 Livermore KE, Munkley J and Elliott JD 2016 Androgen receptor and prostate cancer. AIMS Mol. Sci. 3 280–299 Fang L, Xu Y and Zou L 2014 Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-beta1 in gliomas. Biochem. Biophys. Res. Commun. 446 272–279 Frezzetti D, Gallo M, Maiello MR, D’alessio A, Esposito C, Chicchinelli N, Normanno N and De Luca A 2017 VEGF as a potential target in lung cancer. Expert. Opin. Ther. Targets 21 959–966 Garcia-Fernandez J 2005 The genesis and evolution of homeobox gene clusters. Nat. Rev. Genet. 6 881–892 Gehring WJ, Affolter M and Burglin T 1994 Homeodomain proteins. Annu. Rev. Biochem. 63 487–526 Hayashida T, Takahashi F, Chiba N, Brachtel E, Takahashi M, Godin-Heymann N, Gross KW, Vivanco M, Wijendran V, Shioda T, Sgroi D, Donahoe PK and Maheswaran S 2010 HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc. Natl. Acad. Sci. USA 107 1100–1105 Hemmings BA and Restuccia DF 2012 PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol. 4 a011189 Hoshino Y, Hayashida T, Hirata A, Takahashi H, Chiba N, Ohmura M, Wakui M, Jinno H, Hasegawa H, Maheswaran S, Suematsu M and Kitagawa Y 2014 Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication. Mol. Cancer 13 102 Huang K, Yuan R, Wang K, Hu J, Huang Z, Yan C, Shen W and Shao J 2014 Overexpression of HOXB9 promotes metastasis and indicates poor prognosis in colon cancer. Chin. J Cancer Res. 26 72–80 Javed S and Langley SE 2014 Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection. BJU Int. 113 535–540 Kwon OS, Oh E, Park JR, Lee JS, Bae GY, Koo JH, Kim H, Choi YL, Choi YS, Kim J and Cha HJ 2015 GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma. Oncotarget 6 41916–41928 Luo M, Liu Q, He M, Yu Z, Pi R, Li M, Yang X, Wang S and Liu A 2017 Gartanin induces cell cycle arrest and autophagy and suppresses migration involving PI3K/Akt/mTOR and MAPK signalling pathway in human glioma cells. J. Cell. Mol. Med. 21 46–57 Morgan R, Boxall A, Harrington KJ, Simpson GR, Gillett C, Michael A and Pandha HS 2012 Targeting the HOX/PBX dimer in breast cancer. Breast Cancer Res. Treat. 136 389–398 Nagel S, Burek C, Venturini L, Scherr M, Quentmeier H, Meyer C, Rosenwald A, Drexler HG and Macleod RA 2007 Comprehensive analysis of homeobox genes in Hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1. Blood 109 3015–3023 Paduch R 2016 The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell. Oncol. (Dordr) 39 397–410 Rahman FU, Ali A, Khan IU, Duong HQ, Guo R, Wang H, Li ZT and Zhang DW 2017 Novel phenylenediamine bridged mixed ligands dimetallic square planner Pt(II) complex inhibits MMPs expression via p53 and caspase-dependent signaling and suppress cancer metastasis and invasion. Eur. J Med. Chem. 125 1064–1075 Seki H, Hayashida T, Jinno H, Hirose S, Sakata M, Takahashi M, Maheswaran S, Mukai M and Kitagawa Y 2012 HOXB9 expression promoting tumor cell proliferation and angiogenesis is associated with clinical outcomes in breast cancer patients. Ann. Surg. Oncol. 19 1831–1840 Semenza GL 2003 Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3 721–732 Sha L, Dong L, Lv L, Bai L and Ji X 2015 HOXB9 promotes epithelial-to-mesenchymal transition via transforming growth factor-beta1 pathway in hepatocellular carcinoma cells. Clin. Exp. Med. 15 55–64 Shay G, Lynch CC and Fingleton B 2015 Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol. 44–46 200–206 Shrestha B, Ansari KI, Bhan A, Kasiri S, Hussain I and Mandal SS 2012 Homeodomain-containing protein HOXB9 regulates expression of growth and angiogenic factors, facilitates tumor growth in vitro and is overexpressed in breast cancer tissue. FEBS J. 279 3715–3726 Siegel RL, Miller KD and Jemal A 2017 Cancer Statistics 2017. CA Cancer J. Clin. 67 7–30 Singh M, Yelle N, Venugopal C and Singh SK 2017 EMT: Mechanisms and therapeutic implications. Pharmacol. Ther. 182 80–94 Suarez-Carmona M, Lesage J, Cataldo D and Gilles C 2017 EMT and inflammation: inseparable actors of cancer progression. Mol. Oncol. 11 805–823 Tsai JR, Liu PL, Chen YH, Chou SH, Cheng YJ, Hwang JJ and Chong IW 2015 Curcumin inhibits non-small cell lung cancer cells metastasis through the adiponectin/NF-kappab/MMPs signaling pathway. PLoS One 10 e0144462 Vivanco I and Sawyers CL 2002 The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2 489–501 Wang H, Jia XH, Chen JR, Yi YJ, Wang JY, Li YJ and Xie SY 2016 HOXB4 knockdown reverses multidrug resistance of human myelogenous leukemia K562/ADM cells by downregulating P-gp, MRP1 and BCRP expression via PI3K/Akt signaling pathway. Int. J. Oncol. 49 2529–2537 Wang H, Liu G, Shen D, Ye H, Huang J, Jiao L and Sun Y 2015 HOXA1 enhances the cell proliferation, invasion and metastasis of prostate cancer cells. Oncol. Rep. 34 1203–1210 Wu SY, Rupaimoole R, Shen F, Pradeep S, Pecot CV, Ivan C, Nagaraja AS, Gharpure KM, et al. 2016 A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer. Nat. Commun. 7 11169 Xu W, Yang Z and Lu N 2015 A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell. Adh. Migr. 9 317–324 Xue M, Zhu FY, Chen L and Wang K 2017 HoxB9 promotes the migration and invasion via TGF-beta1/Smad2/Slug signaling pathway in oral squamous cell carcinoma. Am. J. Transl. Res. 9 1151–1161 Yang N, Chen J, Zhang H, Wang X, Yao H, Peng Y and Zhang W 2017 LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma. Cell Death Dis. 8 e2975 Yen CN, Cho YS and Kwon HJ 2017 The effect of indatraline on angiogenesis suppression through HIF-1alpha-mediated VEGF inhibition. Biochem. Biophys. Res. Commun. 485 349–354 Zhan J, Wang P, Niu M, Wang Y, Zhu X, Guo Y and Zhang H 2015 High expression of transcriptional factor HoxB9 predicts poor prognosis in patients with lung adenocarcinoma. Histopathology 66 955–965 Zhao Y and Adjei AA 2015 Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist 20 660–673