<p>Interaction Of c-Jun And HOTAIR- Increased Expression Of p21 Converge In Polyphyllin I-Inhibited Growth Of Human Lung Cancer Cells</p>

Abstract

BackgroundLung cancer is a leading cause of cancer-related death worldwide. Previously we demonstrated that polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, inhibited the growth of non-small cell lung cancer (NSCLC) cells through the SAPK/JNK-mediated suppressing p65, DNMT1 and EZH2 expressions. However, the molecular mechanism underlying anti-lung cancer effect by PPI still remain elusive.PurposeIn this current study, we further explored the molecular mechanism underlying the anti-lung cancer effect of PPI.MethodsMTT, Cell-LightTM EdU DNA cell proliferation and colony formation assays were used to measure cell growth. Western blot were used to examine protein levels of c-Jun and p21. The expression level of long non-codingth RNA HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. The p21 promoter activity was measured by Dual-Luciferase Reporter Assay System. The transient transfection experiments were used to silence and overexpression of c-Jun, p21 and HOTAIR. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings.Results We showed that PPI suppressed growth of NSCLC cells. Mechanistically, we observed that PPI reduced expression of HOTAIR, while increased transcription factor c-Jun protein levels. Additionally, PPI also induced protein expression and promoter activity of p21, a cyclin-dependent kinase inhibitor. While exogenously expressed HOTAIR showed no effect on c-Jun levels, silencing of c-Jun significantly reversed the PPI-inhibited HOTAIR expression. Moreover, excessive expressed c-Jun further enhanced PPI-inhibited HOTAIR expression and PPI-induced p21 protein levels. Intriguingly, overexpression of HOTAIR and silencing of c-Jun overcame the PPI-induced p21 protein and promoter activity. Finally, silencing of p21 neutralized the PPI-inhibited cell proliferation. Similar results were also found in one xenograft mouse model.Conclusion Our results demonstrate that PPI inhibits growth of NSCLC cells through regulation of HOTAIR and c-Jun expressions, which lead to induction of p21 gene. The interactions among HOTAIR, c-Jun and p21 regulatory axis converge in the overall anti-lung cancer effect of PPI. This study unveils an additional new mechanism for the anti-lung cancer role of PPI.

RacGAP1 promotes the malignant progression of cervical cancer by regulating AP-1 via miR-192 and p-JNK

“…Phosphorylation of c-Jun by JNK on serine 63 and 73 could increases its stability to a certain extent and increase its transcriptional activity [ 51 , 52 ]. There is evidence that AP-1 formation proteins, especially Jun group proteins, control cell proliferation, migration and invasion through their ability to regulate the expression and function of many genes such as Cyclin D1, p21 cip1/waf1 , p19 ARF , p16, c-Myc, β-catenin, matrix metalloproteinases(MMPs) and VEGFA [ 53 – 59 ]. In our study, Western blot validated that RacGAP1 could influence the expression of c-Jun via miR-192, and phosphorylation of c-Jun via p-JNK separately.…”

Exosomal Long Non-Coding RNAs in Lung Diseases

“…In an NSCLC cell line (PC9), HOTAIR is involved in cellular growth with p65 (RELA), DNMT1, and EZH2. Moreover, HOTAIR can inhibit JUN and CDKN1A [221]. Furthermore, in NSCLC tumors tissues and PC9 cell line, HOTAIR can activate WNT3A, CTNNB1, APC, ABCC1, and ABCB1, and can also promote the expression of 14-3-3σ (SFN) [222,223].…”

Anticancer Effect of Polyphyllin I in Suppressing Stem Cell-Like Properties of Hepatocellular Carcinoma via the AKT/GSK-3β/β-Catenin Signaling Pathway

“…These results provide a novel insight and a basis for new therapeutic strategies for HCC. PPI, a natural bioactive compound (steroidal saponin) that originates from the rhizome of P. polyphylla has previously been confirmed to significantly inhibit several cancers via multiple mechanisms [47]. Available studies have focused on its proapoptotic and resistance inhibition effects in HCC, non-small-cell lung cancer, and colorectal cancer cells [48].…”