PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer

Abstract

Background:MicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation.Methods:NSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7.Results:In this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines.Conclusion:All these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7 may become promising molecular therapies in NSCLC treatment.

Promoter mutation of tumor suppressor microRNA-7 is associated with poor prognosis of lung cancer

“…The relative expression of miR-7 was also assessed by qPCR in 39 lung cancer and 8 normal lung tissue specimens. Consistent with previous findings (14), the relative expression of miR-7 decreased significantly in lung cancer tissues compared with that in normal lung tissues (data not shown). Notably, we found that the expression level of miR-7 in lung cancer tissues with mutation sites was lower compared with that in lung cancer tissues without mutation sites (Fig.…”

“…In lung cancer, recent evidence demonstrated that the expression of miR-7 is decreased in cancer tissues (14). Moreover, miR-7 was found to inhibit the growth and metastasis of lung cancer cells and induce their apoptosis (21).…”

“…miR-7 expression was found to be repressed in lung cancer tissues (7,14). Moreover, miR-7 was able to suppress the growth and metastatic potential of human lung cancer cells in vitro (15).…”

Prognostic Significance of microRNA-7 and its Roles in the Regulation of Cisplatin Resistance in Lung Adenocarcinoma

“…Xiong’ et al showed that miR-7 inhibited the growth of human non-small cell lung cancer A549 cells through targeting BCL-2 [14]. The same research group also identified PA28gamma as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer [45]. Xu and his colleagues reported that miR-7-regulated TLR9 signaling-enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/Akt pathway [46].…”

Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ

“…6D). In fact, REGγ is reported to be regulated by other signals than mutant p53, the most studied is miR-7 [56][57][58], a tumor suppressor in many cancers. Therefore we suppose REGγ could be upregulated by some undetermined molecules in these p53-negative specimens and cells.…”