Exploration on correlation of high DLX2 expression with poor prognosis and cellular proliferation in epithelial ovarian cancers

Objective: It has been found that overexpression of distal-less homeobox 2 (DLX2) is closely correlated with multiple cancers. However, the role of DLX2 in the pathogenesis of ovarian cancers is not known. This study was designed to explore the mechanism of action of DLX2 on cellular proliferation and apoptosis in epithelial ovarian cancers (EOCs). Methods: A total of 119 EOC tissue specimens were analyzed immunohistochemically, and the correlation between DLX2 expressional level and clinicopathological characteristics was determined. Moreover, western blot method was used to measure DLX2 protein in EOC specimen of different grades and EOC cell lines and explore its molecular mechanism of action. Kaplan-Meier survival analysis revealed that overexpression of DLX2 was obviously correlated with an adverse clinical outcome in EOCs (P < 0.01*). Results: DLX2 expressional level had an obvious association with histopathological grade, FIGO stage, ascites and ki-67 expressional level in EOC patients and DLX2 exerted a crucial effect in regulating cellular proliferation in EOCs. Knocking down DLX2 using shRNA-DLX2 reduced the proliferation and enhanced the apoptosis in EOC cells. Conclusion: DLX2 might act as a new prognostic indicator and have an important value for molecular targeted therapeutic drugs in EOCs.

Epithelial ovarian cancer (EOC); DLX2; Proliferation

[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: A Cancer Journal for Clinicians. 2012; 62: 10–29.

[2] Konstantinopoulos PA, Matulonis UA. Current status and evolution of preclinical drug development models of epithelial ovarian cancer. Frontiers in Oncology. 2013; 3: 296.

[3] Panganiban G, Rubenstein JL. Developmental functions of the Distal-less/Dlx homeobox genes. Development. 2002; 129: 4371– 4386.

[4] Sun Y, Lu X, Yin L, Zhao F, Feng Y. Inhibition of DLX4 promotes apoptosis in choriocarcinoma cell lines. Placenta. 2006; 27: 375– 383.

[5] Zhang L, Yang M, Gan L, He T, Xiao X, Stewart MD, et al. DLX4 Upregulates TWIST and enhances tumor migration, invasion and metastasis. International Journal of Biological Sciences. 2012; 8: 1178–1187.

[6] Xu J, Testa JR. DLX5 (Distal-less Homeobox 5) promotes tumor cell proliferation by transcriptionally regulating MYC. Journal of Biological Chemistry. 2009; 284: 20593–20601.

[7] Tan Y, Cheung M, Pei J, Menges CW, Godwin AK, Testa JR. Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling. Cancer Research. 2010; 70: 9197–9206.

[8] Suh Y, Obernier K, Hölzl-Wenig G, Mandl C, Herrmann A, Wörner K, et al. Interaction between DLX2 and EGFR regulates proliferation and neurogenesis of SVZ precursors. Molecular and Cellular Neuroscience. 2009; 42: 308–314.

[9] Green WJ, Ball G, Hulman G, Johnson C, Van Schalwyk G, Ratan HL, et al. KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach. British Journal of Cancer. 2016; 115: 236–242.

[10] Dai Q, Deng J, Zhou J, Wang Z, Yuan X, Pan S, et al. Long non- coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis. Cancer Cell International. 2020; 20: 8.

[11] Morini M, Astigiano S, Gitton Y, Emionite L, Mirisola V, Levi G, et al. Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231. BMC Cancer. 2010; 10: 649.

[12] Xi Q, Huang M, Wang Y, Zhong J, Liu R, Xu G, et al. The expres- sion of CDK1 is associated with proliferation and can be a prognostic factor in epithelial ovarian cancer. Tumor Biology. 2015; 36: 4939–4948.

[13] Yilmaz M, Maass D, Tiwari N, Waldmeier L, Schmidt P, Lehembre F, et al. Transcription factor Dlx2 protects from TGFβ- induced cell-cycle arrest and apoptosis. The EMBO Journal. 2011; 30: 4489–4499.