Suppression of Heterogeneous Nuclear Ribonucleoprotein C Inhibit Hepatocellular Carcinoma Proliferation, Migration, and Invasion via Ras/MAPK Signaling Pathway

Abstract

Hepatocellular carcinoma (HCC), the most common malignant tumor, has high fatality and recurrence rates. Accumulating evidence shows that heterogeneous nuclear ribonucleoprotein C (HNRNPC), which is mainly involved in RNA splicing, export, and translation, promotes progression and metastasis of multiple tumor types; however, the effects of HNRNPC in HCC are unknown. In the present study, high levels of HNRNPC were detected in tumor tissues compared with para-tumor tissues by immunohistochemical and western blot assays. Furthermore, Cox proportional hazards regression models, the Kaplan–Meier method, and clinicopathologic features analysis showed that HNRNPC was not only an independent prognostic factor for both overall and disease-free survival in HCC but also a predictor of large tumor size and advanced tumor stage. Functional experiments revealed that silencing of HNRNPC not only led to arrest of more HCC cells at G0/G1 phase to inhibit their proliferation, but also suppressed EMT process to block their invasion, and migration in vitro; this was related to the Ras/MAPK signaling pathway. In addition, blocking of HCC cell proliferation regulated by HNRNPC silencing was observed in vivo. Finally, rescue tests showed that after recovery of Ras/MAPK signaling pathway activity by treatment with Ras agonists, the proliferation, migration, and invasion suppression of Huh-7 and Hep 3B cell lines caused by HNRNPC knockdown was partially reversed. Taken together, these results indicate that HNRNPC knockdown inhibits HCC cell proliferation, migration and invasion, in part via the Ras/MAPK signaling pathway. Thus, HNRNPC may have an important role in the progression of HCC and represents a promising biomarker for evaluation of prognosis and a potential therapeutic target in HCC patients.

Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma

“…We next focused on the interaction of the hsa_circ_0062682 with proteins previously implicated in the pathology of HCC, namely YBX1 (Y-box-binding protein 1) [ 48 ], IGF2BP1 (Insulin-like growth factor 2 mRNA-binding protein 1) [ 49 ], hnRNP C1/C2 (Heterogeneous nuclear ribonucleoproteins C1/C2) [ 50 ], hnRNP K (Heterogeneous nuclear ribonucleoprotein K) [ 51 ], CSNK2A1 (Casein kinase II subunit alpha) [ 52 ], and ENO1 (Alpha-enolase) [ 53 ]. While YBX1, IGF2BP1, hnRNP C1/C2, and hnRNP K are known to bind RNAs and have roles in RNA metabolism, it has also been shown for CSNK2A1 and ENO1 to be able to bind RNA molecules [ 54 , 55 , 56 ].…”

The Emerging Role of N6-Methyladenosine RNA Methylation as Regulators in Cancer Therapy and Drug Resistance

“…HNRNPA2B1 binds directly to the PFN2 mRNA at the site of the UAGGG sequence of the 3′-UTR and reduces its stability ( Liu et al, 2020b ). Specifically, another report has indicated that decreased HNRNPC expression reduces the activation of the Ras/MAPK signaling pathway ( Hu et al, 2021 ) ( Figure 2 and Table 3 ).…”

CircRNA-Encoded Peptides or Proteins as New Players in Digestive System Neoplasms

“…MAPK signaling cascade, with the Ras-Raf-MEK-MAPK signaling pathway, is involved in various cellular and physiological processes essential to life (46). When extracellular stimulators bind to transmembrane receptors, inactive Ras-GDP in the plasma membrane is converted to active Ras-GTP, which then stimulates active homodimerization consisting of A-Raf, B-Raf, and C-Raf formation of dimeric or heterodimers.…”