Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

Abstract

BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE 2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE 2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P 5.011), especially for those who received 5-fluorouracil-based chemotherapy (P 5.016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLU-SIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-45.

Functional and transcriptomic characterization of cisplatin-resistant AGS and MKN-28 gastric cancer cell lines

“…Transcription factors contribute to drug-induced responses and can induce either transient or acquired drug resistance [60]. Many transcription factors involved in resistance to CDDP have been differentially expressed in this study, such as NRA42 (Nuclear Receptor subfamily 4 group A member 2; P<0.001), an orphan nuclear receptor that confers chemoresistance in GC and colorectal cancer [61,62].…”

Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics

“…Unlike its homologues NR4A1 and NR4A3 where their concomitant loss lead to acute leukemia in murine models (20,21), studies on NR4A2 mostly demonstrated its role as an oncogene. For instance, its forced expression leads to resistance to chemotherapyinduced apoptosis in several human cancer types (18,22). Overexpression of NR4A2 and its association with poor patient outcome have been reported for several human cancer types (15,16,18,22).…”

“…For instance, its forced expression leads to resistance to chemotherapyinduced apoptosis in several human cancer types (18,22). Overexpression of NR4A2 and its association with poor patient outcome have been reported for several human cancer types (15,16,18,22). Given lack of inhibitors for any transcription factors in cancer therapy, development of NR4A2 inhibitors will likely encourage researchers to explore other transcription factors as therapeutic targets.…”

Investigating the Regulation and Function of the NR4A Nuclear Receptors in Cancer

“…The expression of endogenous miR-34a remained low in 5-FU-resistant cells treated with 5-FU, and the restoration of miR-34a or knockdown of SIRT1 in the resistant cells overcame their resistant phenotype. In light of this observation, it would be interesting to study the relationship of miR-34 and NR4A2 with respect to chemoresistance, as increased NR4A2 expression is correlated with worse patient outcomes with regard to 5-FU therapy [93,94,230,231].…”

“…NR4A2 is highly expressed in squamous cell carcinoma (SCC), as compared to normal patient tissues, and prostaglandin-mediated induction of NR4A2 expression in SCC leads to increased resistance to 5-fluorouracil (5-FU) [93]. The effects of NR4A2 on chemoresistance are also seen in colorectal cancers [94,230], and high expression of NR4A2 predicts a poor outcome for gastric cancer patients receiving 5-FU therapy [231]. NR4A2 may mediate these effects through a previously described NR4A2-p53 interaction that serves to suppress p53 transactivation, thereby protecting cells from p53induced apoptosis [95].…”