Linc00887 suppresses tumorigenesis of cervical cancer through regulating the miR-454-3p/FRMD6-Hippo axis

Abstract

Background Emerging evidence suggested that long intergenic noncoding RNA (lincRNA) 00887 (NR_024480) reduced the invasion and metastasis of non-small cell lung cancer by sponging miRNAs degradation. However, the role and regulatory mechanism of linc00887 in the progression of cervical cancer remain largely unknown. Methods In vivo or vitro, RT-qPCR assay was used to detect the expression of linc00887 in human normal (N = 30), cervical cancer tissues (N = 30), human normal cervical epithelial cells (Ect1/E6E7) and cervical cancer cell lines (HeLa, C33A). Then, CCK-8 and Transwell assays were used to examine cell proliferation and invasion when linc00887 was overexpressed or knocked down. In addition, bioinformatics, luciferase reporter gene and pull-down assays were used to predict and validate the relationship between linc00887 and miR-454-3p. Moreover, we detected the expression of miR-454-3p in Ect1/E6E7, HeLa and C33A cells when linc00887 was overexpressed or knocked down. Cell proliferation and invasion were also measured when pcDNA-linc00887 and miR-454-3p were transfected alone or together. Next, miR-454-3p target gene was predicted and validated by bioinformatics and luciferase reporter gene assays. Gain- and loss-of-function experiments were performed in HeLa cells to evaluate the effect of miR-454-3p or linc00887 on the expression of FERM domain containing protein 6 (FRMD6) protein and several key proteins in the FRMD6-Hippo signaling pathway. Results Linc00887 was downregulated in cervical cancer tissues or human cervical cancer cell lines (Hela, C33A) compared with normal tissues or cell lines. Overexpression of linc00887 inhibited proliferation and invasion HeLa and C33A cells, while linc00887 knockdown had the opposite effect. Linc00887 bound with miR-454-3p, and overexpression of miR-454-3p rescued linc00887-induced inhibition proliferation and invasion of HeLa cells. MiR-454-3p targeted and suppressed the expression of FRMD6, and linc00887 suppressed tumorigenesis of cervical cancer through activating the FRMD6-Hippo signaling pathway. Conclusions Linc00887, sponging miR-454-3p, inhibited the progression of cervical cancer by activating the FRMD6-Hippo signaling pathway.

Willin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer’s Disease

“…Recent studies have provided an insight into the endogenous localization of Willin/FRMD6 in the peripheral nervous system (PNS) and central nervous system (CNS) (Figure 2). In the PNS, Willin/FRMD6 expression is observed in fibroblasts and Schwann cells of rat sciatic nerves [21,23] and in the Schwann cell microvilli of myelinated mouse peripheral nerves [37]. Willin/FRMD6 expression in the nervous system.…”

“…Willin/FRMD6 is widely distributed in various tissues and cell types including epithelial cells within the uterus, placenta, cervix, brain, heart, liver, prostate, and lungs [ 1 , 19 , 20 , 21 ]; fibroblasts of the peripheral nerves [ 1 , 21 ]; neurons of the peripheral (PNS) and central nervous systems (CNS) [ 22 , 23 ].…”

“…Within neurons of the PNS, Willin/FRMD6 transcripts are found in the human and mouse sensory ganglia [ 38 , 39 , 40 , 41 ]. Furthermore, Willin/FRMD6 immunoreactivity is observed in the sensory ganglia corresponding to cranial nerves V, IX, and X of rat, xenopus, and humans [ 22 ] and in dorsal root ganglia (DRG), motor neurons, and the axons of the sciatic nerves in mice [ 23 ]. The distribution of Willin/FRMD6 in the periphery is non-homogeneous as it appears to be preferentially expressed in small and medium-sized DRG neurons, many of which are nociceptors [ 23 ] and is exclusively found in small caliber peptidergic fibers of cranial nerves containing both sensory and motor fibers (cranial nerves V, IX, and X) in rats, xenopus, and humans, with the highest immunoreactivity in cranial nerve X [ 22 ].…”

“…Specifically, Willin/FRMD6 expression is found in the cytoplasm and nucleus of neurons throughout the mouse brain ([ 42 ], , accessed on 1 August 2021). Similarly, Willin/FRMD6 is found in the cytoplasm and nucleus, but not the nucleolus, of mice DRG with three distinct staining patterns: cytoplasmic only, nucleus only, and combined cytoplasmic and nuclear staining [ 23 ]. Willin/FRMD6 cytoplasmic staining is vesicular/granular in varicose nerve fibers in the rat CNS and PNS, with younger animals displaying more numerous and intense staining of nerve fibers [ 22 ].…”

“…In this context, Willin/FRMD6 may initiate wound closure in response to nerve injury by inducing fibroblast migration and further downregulation of receptor tyrosine kinase Ephrin B2 and epidermal growth factor receptor [ 21 ]. Neuronal response to peripheral nerve injury appears to involve Willin/FRMD6 cytoplasmic-to-nuclear shuttling [ 23 ], providing evidence of its differing roles depending on subcellular localization. Such differences in function have been observed for other FERM domain proteins including Merlin, which activates Hippo signaling and recruits Par3 and aPKC to E-cadherin-dependent junctions near the plasma membrane and translocates to the nucleus to directly affect transcription of growth-suppressive genes [ 49 ].…”