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Pancreatic neuroendocrine neoplasms (pNENs) are among the most frequently occurring neuroendocrine neoplasms (NENs) and require targeted therapy. High levels of fatty acid binding protein 5 (FABP5) are involved in tumor progression, but its role in pNENs remains unclear. We investigated the mRNA and protein levels of FABP5 in pNEN tissues and cell lines and found them to be upregulated. We evaluated changes in cell proliferation using CCK‐8, colony formation, and 5‐ethynyl‐2′‐deoxyuridine assays and examined the effects on cell migration and invasion using transwell assays. We found that knockdown of FABP5 suppressed the proliferation, migration, and invasion of pNEN cell lines, while overexpression of FABP5 had the opposite effect. Co‐immunoprecipitation experiments were performed to clarify the interaction between FABP5 and fatty acid synthase (FASN). We further showed that FABP5 regulates the expression of FASN via the ubiquitin proteasome pathway and both proteins facilitate the progression of pNENs. Our study demonstrated that FABP5 acts as an oncogene by promoting lipid droplet deposition and activating the WNT/β‐catenin signaling pathway. Moreover, the carcinogenic effects of FABP5 can be reversed by orlistat, providing a novel therapeutic intervention option. This study showed that FABP5 might play a role of oncogene through playing an auxo‐action for the deposition of lipid droplets and FABP5 is involved in activating the WNT/β‐catenin pathway. Moreover, those carcinogenic effects of FABP5 can be reversed by orlistat, providing novel choice for therapeutic intervention.

With the development of functional genomics studies, a mass of long non‐coding RNAs (LncRNA) were discovered from the human genome. Long non‐coding RNAs serve as pivotal regulators of genes that are able to generate LncRNA–binding protein complexes to modulate a great number of genes. Recently, the LncRNA urothelial carcinoma‐associated 1 (UCA1) has been revealed to be dysregulated, which plays a critical role in the development of a few cancers. However, the role of the biology and clinical significance of UCA1 in the tumorigenesis of oral squamous cell carcinoma (OSCC) remain unknown. We found that UCA1 expression levels were upregulated aberrantly in tongue squamous cell carcinoma tissues and associated with lymph node metastasis and TNM stage. We explored the expression, function, and molecular mechanism of LncRNA UCA1 in OSCC. In the present work, we revealed that UCA1 silencing suppressed proliferation and metastasis and induced apoptosis of OSCC cell lines in vitro and in vivo, which might be related to the activation level of the WNT/β‐catenin signaling pathway. Our research results emphasize the pivotal role of UCA1 in the oncogenesis of OSCC and reveal a novel LncRNA UCA1–β‐catenin–WNT signaling pathway regulatory network that could contribute to our understanding in the pathogenesis of OSCC and assist in the discovery of a viable LncRNA‐directed diagnostic and therapeutic strategy for this fatal disease. Our data highlighted the pivotal role of UCA1 in the tumorigenesis of oral squamous cell carcinoma, and revealed a novel LncRNA UCA1‐β‐catenin‐Wnt signaling pathway regulatory network, which may contribute to understand the pathogenesis of oral squamous cell carcinoma.

The transcription factor p300 is reportedly involved in age‐associated human diseases, including intervertebral disc degeneration (IDD). In this study, we investigate the potential role and pathophysiological mechanism of p300 in IDD. Clinical tissue samples were collected from patients with lumbar disc herniation (LDH), in which the expression of p300, forkhead box O3 (FOXO3), and sirtuin 1 (Sirt1) was determined. Nucleus pulposus cells (NPCs) isolated from clinical degenerative intervertebral disc (IVD) tissues were introduced with oe‐p300, oe‐FOXO3, Wnt/β‐catenin agonist 1, C646 (p300/CBP inhibitor), or si‐p300 to explore the functional role of p300 in IDD and to characterize the relationship between p300 and the FOXO3/Sirt1/Wnt/β‐catenin pathway. Also, we established a rat IDD model by inducing needle puncture injuries in the caudal IVDs for further verification of p300 functional role. We found that p300 was downregulated in the clinical tissues and NPCs of IDD. Overexpression of p300 promoted the proliferation and autophagy of NPCs while inhibiting cell apoptosis, which was associated with FOXO3 upregulation. p300 could increase the expression of FOXO3 by binding to the Sirt1 promoter, and thus, contributed to inactivation of the Wnt/β‐catenin pathway. In vivo results further displayed that p300 slowed down the progression of IDD by disrupting the Wnt/β‐catenin pathway through the FOXO3/Sirt1 axis. Taken together, we suggest that p300 can act to suppress IDD via a FOXO3‐dependent mechanism, highlighting a potential novel target for treatment of IDD. p300 upregulates FOXO3, which combines with the SIRT1 promoter to upregulate SIRT1, leading to inactivation of the Wnt/ß‐catenin pathway, thereby promoting autophagy and inhibiting apoptosis of NPCs to protect against IVDD.

Interleukin‐8 (IL‐8), as an inflammatory chemokine, has been previously shown to contribute to tumorigenesis in several malignancies including the ovarian cancer. However, little is known about how IL‐8 promotes the metastasis and invasion of ovarian cancers cells. In this study, we found that IL‐8 and its receptors CXCR1 and CXCR2 were up‐regulated in advanced ovarian serous cancer tissues. Furthermore, the level of IL‐8 and its receptors CXCR1 and CXCR2 expression were associated with ovarian cancer stage, grade and lymph node metastasis. In vitro, IL‐8 promoted ovarian cancer cell migration, initiated the epithelial‐mesenchymal transition (EMT) program and activated Wnt/β‐catenin signalling. However, when treated with Reparixin (inhibitor of both IL‐8 receptors CXCR1 and CXCR2), effect of both endogenous and exogenous IL‐8 was reversed. Together, our results indicated that IL‐8 triggered ovarian cancer cells migration partly through Wnt/β‐catenin pathway mediated EMT, and IL‐8 may be an important molecule in the invasion and metastasis of ovarian cancer.

Cancer is one of the greatest public health challenges. According to the World Health Organization (WHO), 9.6 million cancer deaths have been reported in 2018. The most common cancers include lung, breast, colorectal, prostate, skin (non-melanoma) and stomach cancer. The unbalance of physiological signalling pathways due to the acquisition of mutations in tumour cells is considered the most common cancer driver. The Wingless-related integration site (Wnt)/β-catenin pathway is crucial for tissue development and homeostasis in all animal species and its dysregulation is one of the most relevant events linked to cancer development and dissemination. The canonical and the non-canonical Wnt/β-catenin pathways are known to control both physiological and pathological processes, including cancer. Herein, the impact of the Wnt/β-catenin cascade in driving cancers from different origin has been examined. Finally, based on the impact of Extracellular Vesicles (EVs) on tumour growth, invasion and chemoresistance, and their role as tumour diagnostic and prognostic tools, an overview of the current knowledge linking EVs to the Wnt/β-catenin pathway is also discussed.

The present study aimed to assess the anticancer cell and anticancer stem cell (CSC) effects of GANT61, and its regulatory influence on the Wnt/β-catenin and Notch signalling pathways in colorectal cancer (CRC). HT-29 and HCT-116 cells were treated with 0, 2.5, 5, 10, 20 or 40 µM GANT61, after which relative cell viability and the expression of Gli1, β-catenin and Notch1, as well as the percentage of CD133+ cells, were detected. Subsequently, HT-29/HCT-116 cells and CSCs were treated with 20 µM GANT61, 10 mM of the Wnt/β-catenin pathway agonist HLY78, and 30 mM of the Notch pathway agonist JAG1 (alone or in combination), which was followed by the assessment of cell viability and apoptosis. In both cell lines, GANT61 reduced relative cell viability in a time- and dose-dependent manner, inhibited Gli1, β-catenin and Notch1 expression, and decreased the percentage of CD133+ cells in a dose-dependent manner. Furthermore, HLY78 and JAG1 were both found to improve the relative viability, while downregulating the apoptosis of untreated and GANT61-treated HT-29 and HCT-116 cells. Moreover, Wnt/β-catenin and Notch signalling pathway activity were upregulated in CSCs isolated from HT-29 and HCT-116 cells, compared with the associated control groups. GANT61 also reduced the viability of HT-29 and HCT-116 cells and increased apoptosis, whereas HLY78 and JAG1 treatment resulted in the opposite effect. Moreover, both HLY78 and JAG1 attenuated the effects of GANT61 on cellular viability and apoptosis. In conclusion, GANT61 was found to effectively eliminate cancer cells and CSCs by blocking the Wnt/β-catenin and Notch signalling pathways in CRC.

Osteosarcoma (OS) is a type of malignant primary bone cancer, which is highly aggressive and occurs more commonly in children and adolescents. Thus, novel potential drugs and therapeutic methods are urgently needed. In the present study, we aimed to elucidate the effects and mechanism of melatonin on OS cells to provide a potential treatment strategy for OS. The cell survival rate, cell viability, proliferation, migration, invasion and metastasis were examined by trypan blue assay, MTT, colony formation, wound healing, transwell invasion and attachment/detachment assay, respectively. The expression of relevant lncRNAs in OS cells was determined by real‐time qPCR analysis. The functional roles of lncRNA JPX in OS cells were further examined by gain and loss of function assays. The protein expression was measured by western blot assay. Melatonin inhibited the cell viability, proliferation, migration, invasion and metastasis of OS cells (Saos‐2, MG63 and U2OS) in a dose‐dependent manner. Melatonin treatment significantly downregulated the expression of lncRNA JPX in Saos‐2, MG63 and U2OS cells. Overexpression of lncRNA JPX into OS cell lines elevated the cell viability and proliferation, which was accompanied by the increased metastasis. We also found that melatonin inhibited the OS progression by suppressing the expression of lncRNA JPX via regulating the Wnt/β‐catenin pathway. Our results suggested that melatonin inhibited the biological functions of OS cells by repressing the expression of lncRNA JPX through regulating the Wnt/β‐catenin signalling pathway, which indicated that melatonin might be applied as a potentially useful and effective natural agent in the treatment of OS.

Hepatocellular carcinoma (HCC) is a prevalent solid tumor with a high global death rate. SRY box 9 (SOX9) has been reported as an oncogene in HCC by several studies, but the underlying mechanism remains largely unexplored. Here, we confirmed upregulation of SOX9 in HCC tissues and cell lines and validated that SOX9 facilitates proliferation, migration and invasion in HCC. We subsequently identified that the long non‐coding RNA (lncRNA) SOX9 antisense RNA 1 (SOX9‐AS1) is a neighbor gene to SOX9; SOX9‐AS1 is also upregulated in HCC, and its expression is positively correlated with that of SOX9. In addition, SOX9‐AS1 appears to have prognostic significance in HCC patients. We showed that SOX9‐AS1 aggravates HCC progression and metastasis in vitro and in vivo. We demonstrated that SOX9‐AS1 sponges miR‐5590‐3p to elevate SOX9 expression, and that SOX9 in turn transcriptionally activates SOX9‐AS1. Moreover, we verified that SOX9‐AS1 regulates SOX9 and its known downstream Wnt/β‐catenin pathway so as to facilitate epithelial‐to‐mesenchymal transition. The results of our rescue assays suggest that SOX9‐AS1 regulates HCC progression through SOX9 and the Wnt/β‐catenin pathway. In conclusion, our study demonstrates that a SOX9‐AS1/miR‐5590‐3p/SOX9 positive feedback loop drives tumor growth and metastasis in HCC through the Wnt/β‐catenin pathway, suggesting SOX9‐AS1 as a novel potential prognostic and treatment target for HCC. SOX9 antisense RNA 1 (SOX9‐AS1) upregulated SRY box 9 (SOX9) and activated Wnt/β‐catenin pathway by sponging miR‐5590‐3p to promote cell proliferation, migration and invasion in hepatocellular carcinoma (HCC). SOX9 transcriptionally activated SOX9‐AS1 level so that SOX9‐AS1/miR‐5590‐3p/SOX9 formed a positive feedback loop in HCC cells.

Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican‐3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti‐GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer‐targeted next‐generation sequencing (NGS) and three‐dimensional patient‐derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT‐PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti‐GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS‐08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3‐positive cells was variable in the focal (+; 10%–30%; 8/45), partial (++; 31%–70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10−10). The anti‐GPC3 antibody efficiently inhibits Wnt/β‐catenin signaling and induces apoptosis in GPC3‐positive PDOs and PDXs, as opposed to GPC3‐negative PDOs and PDXs. The high frequency of GPC3 and CD133 co‐expression and the effectiveness of anti‐wild‐type GPC3‐Ab therapy in GPC3‐positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma. Lack of molecular target is a tricky problem in osteosarcoma treatment. In this study, we report (1) high frequency of GPC3 detection (73.77%; 45/61) and its overlapped expression with CD133 in OSs; (2) successful generation of patient‐derived organoids (PDOs) from 24 human osteosarcoma cases (OSs) as ex vivo experimental model; (3) the effectiveness of anti‐GPC3 strategy against GPC3‐expressing OS PDOs and PDXs, accompanied with suppressed Wnt/β‐catenin signaling. We therefor propose that GPC3 would be a promising target for personalized OS therapy.

Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β‐catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β‐catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a treatment. DAG and ceramide enhanced Wnt/β‐catenin signaling by inducing caveolin‐mediated endocytosis of the canonical Wnt‐receptor complex, while their depletion suppressed the signaling activity along with a reduction of caveolin‐mediated endocytosis in SNU475 and HepG2 cells. Moreover, depletion of DAG and ceramide significantly impeded the proliferation, tumor growth, and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth.