Overexpression of DLX2 is associated with poor prognosis and sorafenib resistance in hepatocellular carcinoma.
The mechanism underlying poor prognosis and sorafenib resistance in patients with hepatocellular carcinoma (HCC) is unknown and, to date, no useful predictive biomarkers of sorafenib resistance have been identified. Distal-less homeobox 2 (DLX2) is a transcription factor involved in cell cycle regulation that is closely correlated with cancer prognosis. In this study, we showed that DLX2 is overexpressed in HCC tissues and cell lines and that the level of DLX2 overexpression is positively correlated with histological grade, metastasis and Ki67 expression, which are indicators of poor prognosis. We also found that DLX2 accumulates in proliferating HCC cells, where it is associated with the expression of proliferating cell nuclear antigen (PCNA), Cyclin D1 and Cyclin A. Flow cytometry and cell counting kit-8 (CCK-8) assays indicated that DLX2 depletion causes cell cycle arrest at the G1 phase and hinders cell proliferation. Moreover, the sensitivity of HCC cells to sorafenib is restored when the DLX2 gene is knocked down using a short interfering RNA. We demonstrated that DLX2 facilitates sorafenib resistance by promoting the expression of markers of epithelial-mesenchymal transition and by activating the extracellular signal-regulated protein kinase pathway. Our findings reveal that DLX2 plays a regulatory role in HCC cell proliferation and suggests that targeting DLX2 represents a novel strategy to increase sorafenib efficacy in the management of HCC. In conclusion, DLX2 is a novel marker of poor prognosis and sorafenib resistance in patients with HCC.
Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Jinxia
J
Liu
Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Xiaopeng
X
Cui
Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Lishuai
L
Qu
Grade 14, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Lu
L
Hua
Grade 14, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Miaomiao
M
Wu
Grade 15, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
Zhongyi
Z
Shen
Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China. Electronic address: lch670608@sina.com.
Cuihua
C
Lu
Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China. Electronic address: Nirunzhou@yeah.net.
Runzhou
R
Ni
D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011379:Prognosis; D000077157:Sorafenib; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*
C000619438:DLX2 protein, human; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D010671:Phenylurea Compounds; D014157:Transcription Factors; D009536:Niacinamide; D000077157:Sorafenib
Distal-less homeobox 2; Hepatocellular carcinoma; Prognosis; Sorafenib resistance