DAB2IP predicts treatment response and prognosis of ESCC patients and modulates its radiosensitivity through enhancing IR-induced activation of the ASK1-JNK pathway

Abstract

Background Disabled homolog 2 interacting protein (DAB2IP) plays a tumor-suppressive role in several types of human cancers. However, the molecular status and function of the DAB2IP gene in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy is rarely reported. Methods We examined the expression dynamics of DAB2IP by immunohistochemistry (IHC) in 140 ESCC patients treated with definitive chemoradiotherapy. A series of in vivo and in vitro experiments were performed to elucidate the effect of DAB2IP on the chemoradiotherapy (CRT) response and its underlying mechanisms in ESCC. Results Decreased expression of DAB2IP in ESCCs correlated positively with ESCC resistance to CRT and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Furthermore, the therapeutic sensitivity of CRT was substantially increased by ectopic overexpression of DAB2IP in ESCC cells. In addition, knockdown of DAB2IP dramatically enhanced resistance to CRT in ESCC. Finally, we demonstrated that DAB2IP regulates ESCC cell radiosensitivity through enhancing ionizing radiation (IR)-induced activation of the ASK1-JNK signaling pathway. Conclusions Our data highlight the molecular etiology and clinical significance of DAB2IP in ESCC, which may represent a new therapeutic strategy to improve therapy and survival for ESCC patients.

An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications

“…In esophageal squamous cell carcinoma (ESCC) cells, expression of DAB2IP was shown to reduce resistance to ionizing radiation; in vitro, DAB2IP overexpressing cells displayed higher apoptosis after cisplatin treatment and IR exposure. In nude mice, DAB2IP expression did not affect the growth rate of ESCC xenografts, but after IR treatment DAB2IP-expressing tumors were significantly reduced compared to controls [44].…”

“…Enhanced IR-induced activation of the ASK1/JNK pathway Increased apoptosis after cisplatin treatment and ionizing radiation (IR) in vitro; reduced tumor size after IR in vivo [44] Colorectal cancer Inhibition of AKT and ERK activation; regulation of HSP90AA1/SRP9/ASK1/JNK signaling axis Decreased cell growth and migration in vivo and increased sensitivity to chemotherapeutic drugs in vitro [42] Inducing c-Myc degradation via GSK3βmediated phosphorylation…”

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

“…In our study, it presented a higher level in high-risk BC patients, which also hinted at the inferior outcome in this group and was listed as a potential target for BC treatment. DAB2IP belonged to the Ras GTPase-activating protein family and played an anti-tumor role in multiple cancers, such as esophageal squamous cell carcinoma ( 48 ), and triple-negative breast cancer ( 49 ). Additionally, in TBNC, it was shown that the expression of DABI2P was able to alleviate chemoresistance ( 49 ), which means that it was a promising market to improve the prognosis of BC patients.…”

DAB2IP suppresses invadopodia formation through destabilizing ALK by interacting with USP10 in breast cancer

“…DAB2IP was first reported as a DOC-2/DAB2 interacting protein and has been shown to suppress cell proliferation and metastasis. 18 , 19 , 20 , 21 As a scaffold protein, DAB2IP comprises multiple domains involved in various pro-oncogenic signaling pathways, including β-catenin/TCF, 22 NF-κB signaling, 23 ASK1/JNK, 44 and PI3K/AKT. 45 Considering that the DAB2IP protein itself has no kinase function, we screened for potential tyrosine kinases using a RTK phosphorylation antibody microarray.…”