Abstract
Studies have suggested a possible correlation between the newly identified E3 ubiquitin ligase ring finger protein 146 (RNF146) and tumor development. However, until now, studies on RNF146 have been restricted to poly(ADP-ribosyl)ation and ubiquitin ligation, whereas the role of RNF146 in tumor biology has rarely been reported. In the present study, the role of RNF146 in non-small cell lung cancer (NSCLC) was investigated. The results showed that the expression of RNF146 was increased in clinical lung cancer samples and cell lines. RNF146 expression correlated with tumor size, differentiation level, lymphatic metastasis, pTNM staging, and prognosis of patients in stage I. RNF146 expression was negatively correlated with Axin expression but positively correlated with the nuclear expression of β-catenin in NSCLC tissues. RNF146 downregulated the expression of Axin in lung cancer cell lines and induced the expression and nuclear distribution of β-catenin. Overexpression of RNF146 in NSCLC cell lines increased the levels of cyclinD1, cyclinE, and CDK4, promoted cell cycle G0/G1-S transitions, and regulated cell proliferation. Overexpression of RNF146 led to upregulated levels of matrix metalloproteinases 2 and 7 and enhanced lung cancer cell invasiveness, events that were mediated by the classical Wnt/β-catenin signaling pathway. In summary, the data in the present study indicate that RNF146 regulated the development and progression of NSCLC by enhancing cell growth, invasion, and survival, suggesting that RNF146 may be a potential treatment target in NSCLC.
Highlights
E3 ubiquitin ligases play important roles in regulating cell functions including proliferation, cell cycle arrest, and apoptosis
The expression of RING finger protein 146 (RNF146) was analyzed in the HBE and non-small cell lung cancer (NSCLC) cell lines
Different expression levels of RNF146 were observed among the NSCLC cell lines (Figure 1C)
Summary
E3 ubiquitin ligases play important roles in regulating cell functions including proliferation, cell cycle arrest, and apoptosis. They may have additional functions that depend on the identity of their substrates. If an E3 ubiquitin ligase targets an oncogene for degradation, it may be considered a tumor suppressor. If an E3 uniquitin ligase degrades a tumor suppressor protein, it may be considered an oncogene. Many proteins containing RING-finger domains possess ubiquitin ligase activity, some of which participate in tumorigenesis and tumor metastasis. The newly identified E3 ubiquitin ligase RING finger protein 146 (RNF146) interacts with poly(ADP-ribose) (PAR) through a PAR-binding motif in the Trp-Trp-Glu (WWE) domain. As a poly(ADPribosyl)ation (PARsylation)-directed E3 ubiquitin ligase, RNF146 regulates the Tankyrase-dependent degradation of Axin and positively regulates the Wnt signaling pathway [1]
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