LINC00707 promotes hepatocellular carcinoma progression through activating ERK/JNK/AKT pathway signaling pathway

Increasing evidence has demonstrated that abnormal expression of lncRNA is correlated with various malignant tumors, including hepatocellular carcinoma (HCC). Our current study was aimed to investigate the role of LINC00707 in HCC development. We observed that LINC00707 was upregulated in HCC cell lines compared with normal liver cell lines. Then, Hep3B cells and SNU449 cells were infected with LV-shLINC00707 and LV-LINC00707. LINC00707 silencing could greatly repress the proliferation and colony formation of HCC cells in vitro. On the contrary, overexpression of LINC00707 induced HCC cell proliferation and colony formation. In addition, HCC cell apoptosis was significantly enhanced and HCC cell cycle was blocked in G1 phase by LV-shLINC00707. Hep3B cells and SNU449 cell invasion capacity was restrained by the knockdown of LINC00707, whereas upregulation of LINC00707 exhibited an opposite phenomenon. Accumulating evidence has reported that ERK/JNK/AKT signaling is involved in multiple cancers, including HCC. Here, in our study, we identified that ERK/JNK/AKT signaling was dramatically restrained by silencing of LINC00707 while activated by LV-LINC00707 in HCC cells. Subsequently, an in vivo experiment was conducted, and it demonstrated that LINC00707 could modulate HCC development through activating ERK/JNK/AKT signaling. Taking the above results together, it was implied in our study that LINC00707 contributed to HCC progression through modulating the ERK/JNK/AKT pathway.     

Overexpression of LINC00037 represses cervical cancer progression by activating mTOR signaling pathway

Long non-coding RNAs have been reported to play crucial roles in tumorigenesis including cervical cancer. LINC00037 has been identified as a significant regulator in several cancers. Our study was aimed to investigate the function of LINC00037 in cervical cancer progression. LINC00037 was significantly downregulated in human cervical cancer cells (HeLa, HCC94, HT-3, Caski, and SiHa cells) compared with the ectocervical epithelial cells (End1/E6E7 cells). Overexpression of LINC00037 was able to inhibit cervical cancer cell proliferation, induce cell apoptosis, and restrain the cell migration/invasion capacity. Reversely, knockdown of LINC00037 exhibited an opposite process in vitro. mTOR has been recognized as an atypical serine/threonine kinase that is involved in regulating significant cellular functions. In our present study, we observed that the mTOR signaling pathway was strongly activated in human cervical cancer cells. Meanwhile, upregulation of LINC00037 contributed to the inactivation of mTOR signaling whereas downregulation of LINC00037 activated the pathway. Subsequently, in vivo animal models using SiHa cells were established and we proved that LINC00037 repressed cervical cancer progression via targeting the mTOR signaling pathway. All these findings implied that LINC00037 could regulate cervical cancer pathogenesis via mTOR signaling. In conclusion, a novel role of LINC00037 was manifested in cervical cancer progression.     

LINC00665/miR-379-5p/GRP78 regulates cisplatin sensitivity in gastric cancer by modulating endoplasmic reticulum stress

Cytotechnology - Acquired resistance to cisplatin (DDP)-based chemotherapy greatly hinders the treatment of gastric cancer (GC). LINC00665 serves as an oncogene in GC. Hence, the current study was...     

Down-regulated expression of LINC00518 prevents epithelial cell growth and metastasis in breast cancer through the inhibition of CDX2 methylation and the Wnt signaling pathway

Breast cancer (BC)-related mortality is associated with the potential metastatic properties of the primary breast tumors. The following study was conducted with the main focus on the effect of LINC00518 on the growth and metastasis of BC epithelial cells via the Wnt signaling pathway through regulation of the methylation of CDX2 gene. Initially, differentially expressed long intergenic non-protein coding RNAs (lincRNAs) related to BC were screened out in the Cancer Genome Atlas (TCGA) database, after which we detected the LINC00518 expression and localization in BC tissues and cells. Then the CDX2 positive expression and methylation level were identified. The targeting relationship of LINC00518 and CDX2, and binding methyltransferase in the promoter region were examined. BC epithelial cell proliferation, colony formation ability, invasion, migration and apoptosis were further evaluated. The lincRNA expression data related to BC downloaded from the TCGA database revealed that there was a high expression of LINC00518 in BC, and a negative correlation between LINC00518 and CDX2. In addition, LINC00518 promotes CDX2 methylation by recruiting DNA methyltransferase through activating the Wnt signaling pathway. The down-regulation of LINC00518 inhibited proliferation, invasion, migration, and EMT of BC epithelial cells while enhancing apoptosis. The inhibitory effects of LINC00518 down-regulation was reversed by CDX2 down-regulation. In conclusion, our findings revealed that down-regulation of LINC00518 might have the ability to suppress BC progression by up-regulating CDX2 expression through the reduction of methylation and blockade of the Wnt signaling pathway, resulting in the inhibition of proliferation and promotion of apoptosis of BC epithelial cells.     

Blockage of MDM2-mediated p53 ubiquitination by yuanhuacine restrains the carcinogenesis of prostate carcinoma cells by suppressing LncRNA LINC00665

Prostate cancer (PCa) is a challenging issue for men's health worldwide due to its uncontrolled proliferation and high metastatic potential. Increasing evidence has supported plant extracts and natural plant derivatives as promising antitumor therapy with less toxic side effects. Yuanhuacine is an active component isolated from Daphne genkwa and can effectively suppress the tumorigenesis of several cancers. However, its role in PCa remains unclear. In this study, yuanhuacine dose-dependently inhibited the proliferation and induced apoptosis of PCa cells. Moreover, yuanhuacine also restrained the invasion and migration of PCa cells. Mechanically, yuanhuacine decreased the ubiquitination and degradation of p53 protein, and ultimately increased p53 levels, which was regulated by inhibiting the phosphorylation and total protein levels of mouse double minute 2 (MDM2). Moreover, elevation of MDM2 reversed the suppressive efficacy of yuanhuacine in PCa cell viability, invasion, and migration. The network pharmacologic and bioinformatics analysis confirmed that MDM2 might be a common target of D. genkwa and LINC00665. Furthermore, yuanhuacine inhibited LINC00665 expression. Upregulation of LINC00665 reversed yuanhuacine-mediated inhibition in MDM2 protein expression and suppressed p53 levels by enhancing its ubiquitination in yuanhuacine-treated cells. Importantly, the inhibitory effects of yuanhuacine on cell viability and metastatic potential were offset after LINC00665 elevation. Together, the current findings highlight that yuanhuacine may possess tumor-suppressive efficacy by inhibiting LINC00665-mediated MDM2/p53 ubiquitination signaling. Therefore, this study indicates that yuanhuacine may be a promising candidate for the treatment of PCa.     

LINC01133 aggravates the progression of hepatocellular carcinoma by activating the PI3K/AKT pathway

LncRNAs exhibit crucial roles in various pathological diseases, including hepatocellular carcinoma (HCC). Therefore, it is significant to recognize the dysregulated lncRNAs in HCC progression. Recently, LINC01133 has been identified in several tumors. However, the biological role of LINC01133 in HCC remains poorly understood. Currently, we focused on the function of LINC01133 in HCC development. We observed that LINC01133 was significantly increased in HCC cells including HepG2, Hep3B, MHCC-97L, SK-Hep-1, and MHCC-97H cells compared with the normal human liver cell line HL-7702. In addition, PI3K/AKT signaling was highly activated in HCC cells. Knockdown of LINC01133 was able to inhibit HCC cell proliferation, cell colony formation, cell apoptosis, and blocked cell cycle arrest in the G1 phase. For another, downregulation of LINC01133 repressed HCC cell migration and invasion. Subsequently, the PI3K/AKT signaling pathway was strongly suppressed by silence of LINC01133 in Hep3B and HepG2 cells. Then, in vivo tumor xenografts models were established using Hep3B cells to explore the function of LINC01133 in HCC progression. Consistently, our study indicated that knockdown of LINC01133 dramatically repressed HCC tumor progression through targeting the PI3K/AKT pathway in vivo. Taken these together, we revealed that LINC01133 contributed to HCC progression by activating the PI3K/AKT pathway.     

Long noncoding RNA DGCR5 represses hepatocellular carcinoma progression by inactivating Wnt signaling pathway

Increasing studies have indicated that long noncoding RNAs (lncRNAs) exert important roles in hepatocellular carcinoma (HCC). Therefore, it is of great significance to identify the dysregulated lncRNAs in HCC. According to the previous reports, it has been suggested that DiGeorge syndrome critical region gene 5 (DGCR5) might participate in HCC and can serve as potential biomarker for HCC. In our current study, we concentrated on the biological function and roles of lncRNA-DGCR5 in HCC. It was indicated that DGCR5 was decreased in HCC tissues and HCC cells including HepG2, Hep3B, MHCC-97L, SNU-449, and SNU-182 cells compared with the normal human liver cell line LO2. Overexpression of DGCR5 was able to restrain HCC growth, migration, and invasion capacity in HepG2 and SNU-449 cells. In addition, whether lncRNA-DGCR5 can regulate Wnt/β-catenin pathway during HCC progression is unclear. In our study, it was found that upregulation of DGCR5 inactivated Wnt signaling pathway through inhibiting β-catenin, cyclin D1 and increasing GSK-3β levels. Subsequently, in vivo tumor xenografts were established using HepG2 cells to investigate the function of DGCR5 in HCC development. Inconsistent with the in vitro findings, increase of DGCR5 dramatically suppressed HCC tumor progression in vivo. Taken these together, it was uncovered in our research that DGCR5 could play tumor suppressive role by targeting Wnt signaling in HCC progression.     

初级纤毛与Wnt信号通路相关性研究进展

初级纤毛是一类以微管为基础结构的细胞器,其来源于细胞的母中心粒,锚定在细胞膜并如“天线”般突出细胞表面。作为细胞感受器,初级纤毛从环境中接受各种信号,传导至细胞内引起细胞反应。近期的研究表明,初级纤毛对与胚胎发育密切相关的Wnt信号通路的传导起重要作用。纤毛的损害可造成Wnt信号通路的异常,并引起胚胎中多类脏器一系列的病理改变,导致初级纤毛相关疾病的发生。文章主要阐述了初级纤毛与Wnt/β-catenin、Wnt/PCP通路及初级纤毛相关疾病之间的关系,并对初级纤毛相关疾病的治疗进行了初步探讨。对初级纤毛与Wnt信号通路关系的深入研究将有助于人们对该类疾病的进一步诊断和治疗。     

Downregulation of long noncoding RNA DGCR5 contributes to the proliferation,migration, and invasion of cervical cancer by activating Wnt signaling pathway

Accumulating research works have reported that long noncoding RNAs (lncRNAs) are involved in various cancers, including cervical cancer. LncRNA DGCR5 has been identified in many cancers. However, the biological role of DGCR5 in cervical cancer remains barely known. We aimed to investigate the biological function of DGCR5 in cervical cancer progression. Here, in our current study, we observed that DGCR5 was downregulated in human cervical cancer cell lines (MS751, SiHa, HeLa, and HT-3) compared with the primary normal cervical squamous cells (NCSC1 and NCSC2). Then, DGCR5 was restrained by transfection with lenti-virus-short hairpin RNA (LV-shRNA) while induced by LV-DGCR5 in HeLa and C33A cells. Silence of DGCR5 obviously induced cervical cancer cell viability and cell proliferation. Reversely, upregulation of DGCR5 inhibited HeLa and C33A cell survival and proliferation. Furthermore, silencing of DGCR5 increased cervical cancer cell colony formation ability and decreased cell apoptosis, whereas its overexpression exhibited an opposite process. Moreover, DGCR5 suppressed migration and invasion capacity of cervical cancer cells. The Wnt signaling is integral in numerous biological processes. Here, we found that Wnt signaling was strongly activated in cervical cancer cells. Downregulation of DGCR5 contributed to cervical cancer progression by activating Wnt signaling. Subsequently, in vivo animal models were used to confirm that DGCR5 suppressed cervical cancer via targeting Wnt signaling. In conclusion, we reported that DGCR5 was involved in cervical cancer progression via modulating the Wnt pathway.     

Long non‐coding RNA LINC01225 promotes proliferation,invasion and migration of gastric cancer via Wnt/β‐catenin signalling pathway

Emerging evidence has classified the aberrant expression of long non‐coding RNAs (lncRNAs) as a basic signature of various malignancies including gastric cancer (GC). LINC01225 has been shown to act as a hepatocellular carcinoma‐related gene, with its expression pattern and biological function not clarified in GC. Here, we verified that LINC01225 was up‐regulated in tumour tissues and plasma of GC. Analysis with clinicopathological information suggested that up‐regulation of LINC01225 was associated with advanced disease and poorer overall survival. Receiver operating characteristic (ROC) analysis showed that plasma LINC01225 had a moderate accuracy for diagnosis of GC. In addition, knockdown of LINC01225 led to retardation of cell proliferation, invasion and migration, and overexpression of LINC01225 showed the opposite effects. Mechanistic investigations showed that LINC01225 silencing inhibited epithelial‐mesenchymal transition (EMT) process and attenuated Wnt/β‐catenin signalling of GC. Furthermore, ectopic expression of Wnt1 or suppression of GSK‐3β abolished the si‐LINC01225‐mediated suppression against EMT, thereby promoting cell proliferation, invasion and migration of GC. In conclusion, LINC01225 promotes the progression of GC through Wnt/β‐catenin signalling pathway, and it may serve as a potential target or strategy for diagnosis or treatment of GC.     

ACVR1-knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice

Osteogenic differentiation refers to the process of bone formation and remodeling, which is controlled by complex molecular mechanisms. Activin A receptor type I (ACVR1) is reported to be associated with osteogenic differentiation. However, the underlying molecular mechanism remains elusive. Therefore, this study evaluates the function of ACVR1 in osteogenic differentiation through the Wnt signaling pathway. The expression of osteocalcin (Oc) and osterix together with osteogenic differentiation and mineralization was examined in ACVR1-knockout (KO) mouse. Furthermore, the Wnt signaling pathway was inhibited in bone marrow stromal cells (BMSCs) of mice to explore the role of the Wnt signaling pathway in osteogenic differentiation by means of alkaline phosphatase (ALP) activity detection and evaluation of mineralized nodules and calcium content. Subsequently, the effect of ACVR1 on the Wnt signaling pathway was assessed by determining the expression of ACVR1, β-catenin, glycogen synthase kinase 3 β (GSK3β), dickkopf-related protein 1 (DKK1), and frizzled class receptor 1 (FZD1). Both their effects on osteogenic differentiation were further evaluated by determination of Oc, osterix, and Runx2 expression. AVCR1 KO mice exhibited increased Oc and osterix expression and promoted bone resorption and formation. ACVR1-knockout was observed to activate the Wnt signaling pathway with an increase of β-catenin and reductions in GSK3β, DKK1, and FZD1. With the inhibited Wnt signaling pathway expression of Oc, osterix, and Runx2 was decreased, and ALP activity, mineralized nodule, and calcium content in cellular matrix were decreased as well, indicating that inactivation of the Wnt signaling pathway reduced the differentiation of BMSCs into osteoclasts. These findings indicate that ACVR1-knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice.     

microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST

Ankylosing spondylitis (AS) refers to a type of arthritis manifested with chronic inflammation of spine joints. microRNAs (MiRNAs) have been identified as new therapeutic targets for inflammatory diseases. In this study, we evaluated the influence of microRNA-96 (miR-96) on osteoblast differentiation together with bone formation in a murine model of AS. The speculated relationship that miR-96 could bind to sclerostin (SOST) was verified by dual luciferase reporter assay. After successful model establishment, the mice with AS and osteoblasts isolated from mice with AS were treated with mimics or inhibitors of miR-96, or DKK-1 (a Wnt signaling inhibitor). The effects of gain- or loss-of-function of miR-96 on the inflammatory cytokine release (IL-6, IL-10, and TNF-α), alkaline phosphatase (ALP) activity, calcium nodule formation, along with the viability of osteoblasts were determined. It was observed that miR-96 might target and regulate SOST. Besides, miR-96 was expressed at a high level in AS mice while SOST expressed at a low level. TOP/FOP-Flash luciferase reporter assay confirmed that miR-96 activated the Wnt signaling pathway. Moreover, AS mice overexpressing miR-96 exhibited increased contents of IL-6, IL-10 and TNF-α, ALP activity, calcium nodule numbers, and viability of osteoblasts. In contrast, inhibition of miR-96 resulted in suppression of the osteoblast differentiation and bone formation. In conclusion, the study implicates that overexpressing miR-96 could improve osteoblast differentiation and bone formation in AS mice via Wnt signaling pathway activation, highlighting a potential new target for AS treatment.     

PKD1 inhibits cancer cells migration and invasion via Wnt signaling pathway in vitro

The approximately 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a large ( approximately 460 kDa) protein, termed polycystin-1 (PC-1), that is responsible for autosomal dominant polycystic kidney disease (ADPKD). The unique organization of its multiple adhesive domains (16 Ig-like domains/PKD domains) suggests that it may play an important role in cell-cell/cell-matrix interactions. Here we demonstrated that PKD1 promoted cell-cell and cell-matrix interactions in cancer cells, indicating that PC-1 is involved in the cell adhesion process. Furthermore in this study, we showed that PKD1 inhibited cancer cells migration and invasion. And we also showed that PC-1 regulated these processes in a process that may be at least partially through the Wnt pathway. Collectively, our data suggest that PKD1 may act as a novel member of the tumor suppressor family of genes.