RDM1 promotes neuroblastoma growth through the RAS–Raf–MEK–ERK pathway

Abstract

Neuroblastoma ( NB ) is an aggressive cancer that originates in the sympathetic nervous system and primarily affects children. Here, we show that high levels of RAD 52 motif containing 1 ( RDM 1; a protein with similarities to RAD 52, which is important for double‐strand DNA repair) are associated with poor clinical outcomes for NB . In addition, RDM 1 −/− cells exhibited increased sensitivity to cisplatin, a common chemotherapy drug, and disruption of RDM 1 suppressed NB cell proliferation. We also report that loss of RDM 1 augmented cell apoptosis and induced cell cycle arrest, and that stable knockdown of RDM 1 significantly inhibited NB tumor growth in a xenograft mouse model. Importantly, we identified that RDM 1 promoted cell proliferation via the RAS –Raf–mitogen‐activated protein kinase kinase ( MEK )–extracellular signal‐regulated kinase ( ERK ) signaling pathway. In conclusion, the current study demonstrates a correlation between DNA damage regulator RDM 1 and the oncogenic RAS –Raf– MEK – ERK pathway in NB .

Association of RDM1 with osteosarcoma progression via cell cycle and MEK/ERK signalling pathway regulation

“…In neuroblastoma, RDM1 is also reported to increase the protein levels of p-ERK and p-MEK. 4 These findings suggest that RDM1 may promote OS progression via activating MEK/ERK signalling pathway.…”

“…In addition, suppression of RDM1 promoted cell apoptosis in 143B and SaoS2 cell lines by analysing caspase 3/7 activity as well as the protein levels of caspase 3 and cleaved caspase 3. Li W et al, 1 Xie G et al 4 and Xu G et al 5 also found that RDM1 knockdown caused cell proliferation inhibition, and cell apoptosis induction in papillary thyroid carcinoma, neuroblastoma, and lung cancer, respectively.…”

“…In papillary thyroid carcinoma, RDM1 is up‐regulated, and RDM1 knockdown caused cell proliferation inhibition, cell apoptosis induction and cell cycle arrest in the G2/M phase 1 . In neuroblastoma, stable knockdown of RDM1 suppresses tumour growth in vivo, and RDM1 promotes cell proliferation through regulating RAS‐Raf‐Mek‐ERK pathway 4 . In lung cancer, RDM1 is highly expressed in cancer cell lines and tissues, and its overexpression is reported to be correlated with histological differentiation, tumour size, lymph node metastasis and tumour‐node‐metastasis (TNM) stage, suggesting RDM1 potentially repairs DNA double‐strand breaks arising through DNA replication, thereby preventing G2/M cell cycle arrest 5 .…”

“…1 In neuroblastoma, stable knockdown of RDM1 suppresses tumour growth in vivo, and RDM1 promotes cell proliferation through regulating RAS-Raf-Mek-ERK pathway. 4 In lung cancer, RDM1 is highly expressed in cancer cell lines and tissues, and its overexpression is reported to be correlated…”

Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer

“…Anomalous activation of the ERK-1/2 pathway has been associated with tumorigenesis (Deschenes-Simard et al, 2014). Hyperactivation of ERK-1/2 signaling has been reported in several malignancies including neuroblastoma, renal, ovarian, breast, lung, and colorectal cancers (Steinmetz et al, 2004;Vicent et al, 2004;Bartholomeusz et al, 2012;Roseweir et al, 2018;Xie et al, 2019;Zhu et al, 2020). ERK-1/2 signaling cascade also promotes the invasive and metastatic abilities of cancer cells (Ward et al, 2001).…”