lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/β-catenin signaling pathway

Lung cancer ranks topmost among the most frequently diagnosed cancers. Despite increasing research, there are still unresolved mysteries in the molecular mechanism of lung cancer. Long noncoding RNA small nucleolar RNA host gene 11 (SNHG11) was found to be upregulated in lung cancer and facilitated lung cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition progression while suppressed cell apoptosis. Moreover, the high expression of SNHG11 was correlated with poor prognosis of lung cancer patients, TNM stage, and tumor size. Further assays demonstrated that SNHG11 functioned in lung cancer cells via Wnt/β-catenin signaling pathway. Subsequently, Wnt/β-catenin pathway was found to be activated through SNHG11/miR-4436a/CTNNB1 ceRNA axis. As inhibiting miR-4436 could only partly rescue the suppression of cell function induced by silencing SNHG11, it was suspected that β-catenin might enter cell nucleus through other pathways. Mechanism investigation proved that SNHG11 would directly bind with β-catenin to activate classic Wnt pathway. Subsequently, in vivo tumorigenesis was also demonstrated to be enhanced by SNHG11. Hence, SNHG11 was found to promote lung cancer progression by activating Wnt/β-catenin pathway in two different patterns, implying that SNHG11 might contribute to lung cancer treatment by acting as a therapeutic target.     

Gastrin-17 induces gastric cancer cell epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway

Journal of Physiology and Biochemistry - Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has...     

A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis

The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis. In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone (NC043) that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin D1 and Survivin , as well as decreases in the protein levels of Cdc25c and Cdc2. NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of β-catenin stability and may be a potential compound for treating colorectal cancer.     

miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.     

LINC00365 promotes colorectal cancer cell progression through the Wnt/β-catenin signaling pathway

In the past decade, substantial evidence established that long noncoding RNAs are serious about mediating the evolution of malignancies. In previous studies, LINC00365, which has not been reported in colorectal cancer (CRC), was selected using the bioinformatics analysis in GSE109454 and GSE41655 data sets. However, the function and mechanism of LINC00365 are still obscure. In our study, LINC00365 was found upregulated in CRC specimens and intimately connected with the prognosis of patients with CRC. In addition, LINC00365 overexpression enhances the cell abilities of proliferation, migration, and invasion in vitro. Meanwhile, mechanistic studies showed that LINC00365 might involve in CRC cell progression by mediating the Wnt/β-catenin pathway. Furthermore, LINC00365 upregulation increased CDK1 protein expression. In conclusion, this study suggests that LINC00365 acts as a vital part in facilitating CRC progression and might play as a therapeutic target for patients with CRC.     

Adipose mesenchymal stem cell-derived exosomes promote cell proliferation,migration, and inhibit cell apoptosis via Wnt/β-catenin signaling in cutaneous wound healing

Cutaneous wounds, a type of soft tissue injury, are difficult to heal in aging. Differentiation, migration, proliferation, and apoptosis of skin cells are identified as key factors during wound healing processes. Mesenchymal stem cells have been documented as possible candidates for wound healing treatment because their use could augment the regenerative capacity of many tissues. However, the effects of exosomes derived from adipose-derived stem cell (ADSC-exos) on cutaneous wound healing remain to be carefully elucidated. In this present study, HaCaT cells were exposed to hydrogen peroxide (H₂O ₂) for the establishment of the skin lesion model. Cell Counting Kit-8 assay, migration assay, and flow cytometry assay were conducted to detect the biological function of ADSC-exos in skin lesion model. Finally, the possible mechanism was further investigated using Western blot assay. The successful construction of the skin lesion model was confirmed by results of the enhanced cell apoptosis of HaCaT cells induced by H ₂O ₂, the increased Bax expression and decreased Bcl-2 expression. CD9 and CD63 expression evidenced the existence of ADSC-exos. The results of functional experiments demonstrated that ADSC-exos could prompt cell proliferation and migration of HaCaT cells, and repress cell apoptosis of HaCaT cells. In addition, the activation of Wnt/β-catenin signaling was confirmed by the enhanced expression of β-catenin at the protein level. Collectively, our findings suggest that ADSC-exos play a positive role in cutaneous wound healing possibly via Wnt/β-catenin signaling. Our study may provide new insights into the therapeutic target for cutaneous wound healing.     

TMPyP4-regulated cell proliferation and apoptosis through the Wnt/β-catenin signaling pathway in SW480 cells

Background: The aim of this study was to investigate the potential effects of the 5, 10, 15, 20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4) on the proliferation and apoptosis of SW480 cells and the underlying mechanisms by which TMPyP4 exerted its actions. Methods: After treated with different doses of TMPyP4, cell viability was determined by MTT method, the apoptosis was observed by flow cytometry (FCM) and the expression of Wnt, GSK-3β, β-catenin and cyclinD1 was measured by RT-PCR and Western blot analysis. Results: The analysis revealed that TMPyP4 potently suppressed cell viability and induced the apoptosis of SW480 cells in a dose-dependent manner. In addition, the downregulation of Wnt, β-catenin and cyclinD1 expression levels was detected in TMPyP4-treated SW480 cells. However, followed by the block of Wnt signaling pathway using siRNA methods, the effects of TMPyP4 on proliferation and apoptosis of SW480 cells were significantly reduced. Conclusion: It indicates that the TMPyP4-inhibited proliferation and -induced apoptosis in SW480 cells was accompanied by the suppression of Wnt/β-catenin signaling pathway. Therefore, TMPyP4 may represent a potential therapeutic method for the treatment of colon carcinoma.     

miR-186 modulates hepatocellular carcinoma cell proliferation and mobility via targeting MCRS1-mediated Wnt/β-catenin signaling

Previous studies have revealed that miR-186 is involved in the pathogenesis of many malignancies. However, the role of miR-186 in hepatocellular carcinoma (HCC) carcinogenesis and its detailed mechanism are poorly understood. This study was to investigate the function of miR-186 in modulating HCC cell proliferation, cell cycle, migration, and invasion. We found that miR-186 was decreased in HCC tissues and cell lines. Loss-of-function experiments showed that reduction of miR-186 dramatically enhanced tumor cell proliferation and metastasis. Besides, miR-186 also participated in the modulation of the cell cycle. In addition, luciferase reporter assays and Western blot analysis showed that MCRS1 was a novel target of miR-186 in HCC cells. Notably, upregulation of miR-186 suppressed the nuclear β-catenin accumulation and blocked the activation of Wnt/β-catenin signaling in HCC cells. Forced MCRS1 expression abrogated the inhibitory effect of miR-186 on cell growth, metastasis and Wnt/β-catenin signaling in HCC cells. Our findings may provide new insight into the pathogenesis of HCC and miR-186/ MCRS1 might function as new therapeutic targets for HCC.     

Wnt/β-catenin signaling pathway in severe preeclampsia

This study aims to elucidate the mechanisms of Wnt/β-catenin signaling pathway in the development of preeclampsia (PE). The mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were determined by real-time PCR in the placentas. Moreover, the expression levels of Wnt1, β-catenin, Dickkopf-1 (DKK1) and glycogen synthase kinase 3β (GSK-3β) proteins were detected by Western blot. Immunohistochemistry was used in placental tissue microarray to localize the expression of Wnt1, β-catenin, DKK1 proteins in the placentas of two groups. Compared with the control placentas, the mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were decreased in the severe preeclamptic placentas. The Western blot results showed that the expression levels of Wnt1, β-catenin, and GSK-3β proteins were significantly elevated in the control group, while the expression level of DKK1 was significantly decreased. In addition, the staining intensity of Wnt1, β-catenin were weaker in the placentas of the severe PE group while the staining intensity of DKK1 was significantly stronger in the placentas of the severe PE group. Wnt/β-catenin signaling pathway may play a significant role in the pathogenesis of PE by regulating the invasion and proliferation of trophoblast.     

Wnt/β-catenin signaling and disease

The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.     

Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer

Aberrant activation of the Wnt/β-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear β-catenin and the induction of its target genes. Apc(min/+) mice are the most commonly used model for colon cancer. They harbor a mutated Apc allele and develop intestinal adenomas and carcinomas during the first months of life. This phenotype is caused by the mutation of the second Apc allele and the consequent accumulation of nuclear β-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear β-catenin levels in colon cancer in vivo. By appropriate breeding of Apc(min/+) mice and Vdr(+/-) mice we have generated animals expressing a mutated Apc allele and two, one, or none Vdr wild type alleles. Lack of Vdr increased the number of colonic Aberrant Crypt Foci (ACF) but not that of adenomas or carcinomas in either small intestine or colon. Importantly, colon ACF and tumors of Apc(min/+)Vdr(-/-) mice had increased nuclear β-catenin and the tumors reached a larger size than those of Apc(min/+)Vdr(+/+). Both ACF and carcinomas in Apc(min/+)Vdr(-/-) mice showed higher expression of β-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced β-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)(2)D(3) to promote the relocation of β-catenin from the nucleus to the plasma membrane and to inhibit β-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear β-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/β-catenin pathway.     

Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6

Kallistatin, a plasma protein, exerts pleiotropic effects in inhibiting angiogenesis, inflammation and tumor growth. Canonical Wnt signaling is the primary pathway for oncogenesis in the mammary gland. In this study, we demonstrate that kallistatin bound to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), thus, blocking Wnt/β-catenin signaling and Wnt-mediated growth and migration in MDA-MB-231 breast cancer cells. Kallistatin inhibited Wnt3a-induced proliferation, migration, and invasion of cultured breast cancer cells. Moreover, kallistatin was bound to LRP6 in breast cancer cells, as identified by immunoprecipitation followed by western blot. Kallistatin suppressed Wnt3a-mediated phosphorylation of LRP6 and glycogen synthase kinase-3β, and the elevation of cytosolic β-catenin levels. Furthermore, kallistatin antagonized Wnt3a-induced expression of c-Myc, cyclin D1, and vascular endothelial growth factor. These findings indicate a novel role of kallistatin in preventing breast tumor growth and mobility by direct interaction with LRP6, leading to blockade of the canonical Wnt signaling pathway.     

Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/β-catenin signaling

Aberrant expression of the guanine nucleotide exchange factor Tiam1 is implicated in the invasive phenotype of many cancers. However, its involvement in thyroid carcinoma and downstream molecular events remains largely undefined. Here, we examined the effects of Tiam1 on the invasiveness and metastasis of thyroid carcinoma in vitro and in vivo and explored the underlying mechanisms by investigating the regulation of Tiam1 expression and the downstream pathways affected. Our results showed that Tiam1 knockdown inhibited the migratory and invasive capacity of thyroid cancer cells, suppressed epithelial-mesenchymal transition (EMT), and inhibited Wnt/β-catenin signaling in vitro. Moreover, Tiam1 knockdown suppressed liver metastasis development in vivo. The effects of Tiam1 on metastasis and EMT mediated by the Wnt/β-catenin pathway were reversed by Rac1 silencing, suggesting that the prometastatic effect of Tiam1 is mediated by the activation of Rac1. These results indicate that Tiam1 may be a prognostic factor and potential therapeutic target for the treatment of thyroid cancers.     

microRNA-383 regulates cell viability and apoptosis by mediating Wnt/β-catenin signaling pathway in non–small cell lung cancer

The aim of this study was to investigate the roles of microRNA-383 (miRNA-383) in progression of non–small cell lung cancer (NSCLC) and the potential mechanism. The expressions of miR-383 and Wnt1 protein were detected in lung cancer tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. After the transfection of miR-383 mimics, si-Wnt1 or miR-383+Wnt1, the viability and apoptosis of NSCLC cells were detected by cell counting kit-8 and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling, respectively. The interaction between miR-383 and Wnt1 was investigated by luciferase activity and Western blot analysis. Cells stably transfected with miR-383 mimics were inoculated into the right axillary of nude mice by subcutaneous injection. The tumor volume and weight were measured, and the expressions of miR-383, Wnt1, β-catenin, and cyclin D1 were detected by qRT-PCR and Western blot analysis. The expression of miR-383 was significantly decreased, and the level of Wnt1 was significantly increased (P < 0.05) in lung cancer tissues and cells. Upregulation of miR-383 or inhibition of Wnt1 expression inhibited the cell viability and induce apoptosis in NSCLC cells. Moreover, Wnt1 was the target gene of miR-383, and its overexpression weakened the regulatory effect of miR-383 on cell viability and apoptosis in NSCLC cells. Besides, the addition of miR-383 decreased the tumor volume and size and inhibited the expressions of Wnt1, β-catenin, and cyclin D1 at the protein level in nude mice. Collectively, miR-383 induced apoptosis and inhibited cell viability as well as tumorigenic capacity in nude mice via regulating the Wnt/β-catenin signaling pathway.     

lncRNA MSC-AS1 activates Wnt/β-catenin signaling pathway to modulate cell proliferation and migration in kidney renal clear cell carcinoma via miR-3924/WNT5A

Kidney renal clear cell carcinoma (KIRC) is the most general subtype of renal cell carcinoma, which composes about 1/20 of adult malignancies. The anomaly of long noncoding RNAs (lncRNAs) expression is proved to mediate cancer progression of various types. The function and mediation mechanism of MSC-AS1 has rarely been detected in KIRC before. This study started with the mediation of MSC-AS1 on cell function. In this study, MSC-AS1 was dramatically upregulated in KIRC and correlated with dismal prognosis of KIRC patients. Knockdown of MSC-AS1 would suppress the proliferative and migratory properties of KIRC cells. MSC-AS1 was found to directly downregulate miR-3924 expression while miR-3924 directly downregulated WNT5A expression. Meanwhile, MSC-AS1 could promote the expression of WNT5A, indicating the existence of MSC-AS1/miR-3924/WNT5A. Further assays indicated that MSC-AS1 could enhance Wnt/β-catenin pathway. By means of rescue assays, the mediation of MSC-AS1/miR-3924/WNT5A/β-catenin axis on KIRC cell proliferation, migration and migration was verified. This study revealed that MSC-AS1 regulates KIRC cell proliferation and migration via miR-3924/WNT5A/β-catenin axis. MSC-AS1 might contribute to new strategies for KIRC treatment.     

Estrogen receptor alpha regulates the Wnt/β-catenin signaling pathway in colon cancer by targeting the NOD-like receptors

It has been reported that estrogen receptors (ERs) participate in carcinogenesis by directly regulating NOD-like receptors (NLRs). However, the expression profiles of ERs and NLRs in tumor and the ER-NLR regulated signaling pathway are not clear. In this study, we summarized gene expression profiles of ERs and NLRs across normal and tumor tissue by comprehensive data mining. Then we explored the ER-NLR regulated signaling pathway by RNA sequencing (RNA-seq). The results showed that the NLRs and ERs were differentially expressed in different neoplasm tissues. Such expression discrepancies might influence inflammatory regulation and tumorigenesis. Importantly, we identified that ER-NLR regulate Wnt/β-catenin pathway in colon cancer. Taking colon adenocarcinoma (COAD) as example, we found that Wnt2b/LRP8/Dvl1/Axin2/GSK3a/APC/β-catenin genes were differentially expressed in ER^−/− mouse colon tissue and colon cancer cells. The selective ERα antagonist could significantly decrease Wnt2b/LRP8/Dvl1 expression, increase destruction complex (Axin2/GSK3a/APC) expression, and promote degradation of β-catenin in colon carcinoma cell by inhibited NLRP3 expression. In short, the research demonstrates that NLRs are potential biomarkers for cancer, and ERs can regulate the Wnt/β-catenin signaling pathway in cancer by targeting the NLRs. Our results provide a possible signaling pathway in which ER-NLR is correlated with Wnt/β-catenin.     

Long noncoding RNA LINC00961 inhibited cell proliferation and invasion through regulating the Wnt/β-catenin signaling pathway in tongue squamous cell carcinoma

Tongue squamous cell carcinoma (TSCC) is the most frequent style of oral squamous cell carcinoma. However, the molecular mechanisms and function of LINC00961 in the TSCC progression remain unknown. In this study, we proved that LINC00961 expression was downregulated in TSCC cells (Tca8113, SCC1, SCC-4, and SCC-15) compared with normal tissue. In addition, we showed that LINC00961 expression was downregulated in TSCC samples compared with matched normal tissues. Moreover, ectopic expression of LINC00961 decreased TSCC cell growth and invasion and suppressed epithelial-mesenchymal transition in TSCC cell. Furthermore, we indicated that overexpression of LINC00961 decreased β-catenin expression. Knockdown of LINC00961 promoted cell proliferation and invasion partly via promoting the Wnt/β-catenin signaling pathway. These results suggested that LINC00961 was downregulated in TSCC tissues and acted as a tumor suppressor gene in the development of TSCC.     

Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment

The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells'' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.     

Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway

Curcumin, a naturally occurring phenolic compound, has a diversity of antitumor activities. It has been previously demonstrated that curcumin can inhibit the invasion and metastasis of tumors through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). However, the specific roles and mechanisms of curcumin in regulating the malignant behaviors of non-small cell lung cancer (NSCLC) cells still remain unclear. In this study, we found that curcumin could inhibit the proliferation and invasion of NSCLC cells and induce G0/G1 phase arrest. Metastasis-associated protein 1 (MTA1) overexpression has been detected in a wide variety of aggressive tumors and plays an important role on cell invasion and metastasis. Our results showed that curcumin could effectively inhibit the MTA1 expression of NSCLC cells. Further research on the subsequent mechanism showed that curcumin inhibited the proliferation and invasion of NSCLC cells through MTA1-mediated inactivation of Wnt/β-catenin pathway. Wnt/β-catenin signaling was reported to play a critical cooperative role on promoting lung tumorigenesis. Thus, these investigations provided novel insights into the mechanisms of curcumin on inhibition of NSCLC cell growth and invasion and showed potential therapeutic strategies for NSCLC.