Heterogeneous nuclear ribonucleoprotein A2/B1 regulates the ERK and p53/HDM2 signaling pathways to promote the survival, proliferation and migration of non‑small cell lung cancer cells

Kim,Min Kyu; Choi,Mun Ju; Lee,Hyun Min; Choi,Hong Seo; Park,Young-Kwon; Ryu,Chun Jeih

doi:10.3892/or.2021.8104

Heterogeneous nuclear ribonucleoprotein A2/B1 regulates the ERK and p53/HDM2 signaling pathways to promote the survival, proliferation and migration of non‑small cell lung cancer cells

Authors:
- Min Kyu Kim
- Mun Ju Choi
- Hyun Min Lee
- Hong Seo Choi
- Young-Kwon Park
- Chun Jeih Ryu
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Affiliations: Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul 05006, Republic of Korea, Prevention and Management Center, Ulsan University Hospital, Ulsan 44033, Republic of Korea
Published online on: June 7, 2021 https://doi.org/10.3892/or.2021.8104
Article Number: 153

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Abstract

Lung cancer is the most frequent cause of cancer‑associated mortality worldwide. Upregulation of heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) has been reported in non‑small cell lung cancer (NSCLC) cells, but its contribution to NSCLC remains poorly understood. hnRNPA2/B1 is involved in carcinogenesis by interacting with a number of proteins; however, little is known about its interaction with p53. The results of the present study revealed that hnRNPA2/B1 expression levels were upregulated in NSCLC cells under tumorsphere culture conditions and cisplatin treatment compared with those in cells under the adherent condition and dimethyl sulfoxide treatment, respectively, suggesting that hnRNPA2/B1 expression is induced under stress conditions. hnRNPA2/B1 knockdown decreased the number and size of NSCLC cell colonies in a clonogenic survival assay and led to a decreased migratory potential of NSCLC cells, suggesting that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells. hnRNPA2/B1 knockdown induced G₀/G₁ phase arrest in NSCLC cells through cyclin E degradation and phosphorylation of cyclin‑dependent kinase 2. In addition, hnRNPA2/B1 knockdown inhibited extracellular signal‑regulated kinase (ERK)1/2 phosphorylation, suggesting that hnRNPA2/B1 may promote the G₁/S phase transition in NSCLC cells through ERK signaling. hnRNPA2/B1 knockdown resulted in increased expression levels of p21 and p27 in NSCLC cells, as well as p53 induction and phosphorylation. Additionally, hnRNPA2/B1 knockdown inhibited human double minute 2 protein (HDM2) stability and phosphorylation, whereas overexpression of hnRNPA2 induced the opposite effects. These results suggested that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells through preventing the activation of p53, which is induced by ERK‑mediated HDM2 activation. The results of the present study also indicated that the components of the hnRNPA2/B1/ERK/p53/HDM2 signaling pathway may be novel potential molecular targets for the treatment of patients with NSCLC.

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