The Role of NR1D1 and NR2E3 in retinoblastoma progression

(Image Credit: AdobeStock/MQ-Illustrations)

Nuclear receptor subfamily 1 group D member 1 (NR1D1) and nuclear receptor subfamily 2 group E member 3 (NR2E3), orphan nuclear receptors that are ubiquitously expressed and involved in embryogenesis, differentiation, and homeostasis maintenance,¹ were found to have low levels of expression in patients with advanced retinoblastoma,² according to co-first authors Jie Ding, MD, and Jie Sun, MD. Both investigators are from the Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China.

The investigators explained that the survival rate of patients with retinoblastoma has improved significantly as a result of intra-arterial chemotherapy and enucleation surgery. However, patients with extensive choroidal and optic nerve invasion have challenging prognoses. That was the rationale for their study, ie, more treatment strategies are needed to improve the outcomes in patients who have significant invasion. They believe that studying the invasion features of retinoblastoma is crucial for identifying potential therapeutic options.

The findings from a number of recent studies have suggested that NR1D1 and NR2E3 may be critical in human cancers. “It has been demonstrated that NR1D1 […] inhibits the growth of ovarian cancer and is related to the prognosis of breast cancer.^3,4 NR2E3 has previously been defined as a photoreceptor-specific nuclear receptor, acting as an essential character in the development of normal retina as well as in the suppression of liver and breast cancer.^5,6 These findings suggest that NR1D1 and NR2E3 may play critical roles in tumorigenesis and cancer progression, highlighting their therapeutic relevance,” the investigators explained.

It currently is unknown how NR1D1 and NR2E3 affect the progression of retinoblastoma.

In the study under discussion, the investigators measured the expression levels of NR1D1 and NR2E3 using immunohistochemical assays and then analyzed their association with the clinicopathological characteristics of patients with retinoblastoma.

The results showed that in the 51 patients who were included in the analysis, the expression levels of NR1D1 and NR2E3 were significantly (P = 0.004 and P = 0.024, respectively) lower in the tumor tissue compared with the normal retinal tissue.

They also found that advanced stages of retinoblastoma (P = 0.007, P = 0.015, respectively), choroidal infiltration (P = 0.003, P = 0.029, respectively), and optic nerve infiltration (P = 0.036, P = 0.003, respectively) also were associated with significantly lower expression levels of NR1D1 and NR2E3.

Finally, low NR2E3 expression was associated with high-risk pathology (P = 0.025) and necrosis (P = 0.035) of the retinoblastoma tissues.

The investigators believe that their results “may provide insights into the unique features of choroidal and optic nerve invasion in retinoblastoma and lead to the development of novel therapeutic targets for retinoblastoma treatment.”

References:

1. Wu D, Cheung A, Wang Y, Yu S, Chan FL. The emerging roles of orphan nuclear receptors in prostate cancer. Biochim Biophys Acta. 2016;1866:23–36.

2. Ding J, Sun J, Ma RQ, et al. Low expression of NR1D1 and NR2E3 is associated with advanced features of retinoblastoma. Int Ophthalmol. 2024;44:133; https://doi.org/10.1007/s10792-024-03055-3

3. Na H, Han J, Ka N-L, et al. High expression of NR1D1 is associated with good prognosis in triple-negative breast cancer patients treated with chemotherapy. Breast Cancer Res. 2019;21:127.

4. Wang H, Fu Y. NR1D1 suppressed the growth of ovarian cancer by abrogating the JAK/STAT3 signaling pathway. BMC Cancer. 2021;21:871.

5. Park Y-Y, Kim K, Kim S-B, et al. Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer. EMBO Mol Med. 2012;4:52–67.

6. Khanal T, Choi K, Leung Y-K, et al. Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer. Sci Rep. 2017;7:10662.