Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

/pdf/wnt-b-catenin-signaling-in-cancers-and-targeted-therapies-pr1yeroi4p.pdf

Wnt/β-catenin signaling in cancers and targeted therapies.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.

/pdf/the-role-of-il-6-jak2-stat3-signaling-pathway-in-cancers-150coa2p.pdf

The role of IL-6/JAK2/STAT3 signaling pathway in cancers

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

https://www.mdpi.com/1422-0067/20/17/4242/pdf

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Oxidative stress, a hallmark of many diseases, damages the endothelial glycocalyx, resulting in vascular dysfunction. Studying the mechanistic link between oxidative stress and endothelial glycocal...

Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx

Recent advances in pancreatic cancer: biology, treatment, and prevention.

Drug resistance is a major impediment to successful chemotherapy in pancreatic cancer (PC) patients. We investigated the effect of Wnt/β-catenin signaling inhibition by wnt-c59 on chemoresistance in a trichostatin A-resistant Panc-1 cell line (Panc-1/TSA). Panc-1/TSA cells were treated with the Wnt/β‑catenin signaling inhibitor wnt-c59 (10 µmol · l-1) and/or trichostatin A (TSA; 10 µmol · l-1) for 24 h. CCK-8 assay was utilized to analyze the interactive effect of TSA and wnt-c59 on induction of apoptosis of the Panc-1/TSA cells. Cell apoptosis was measured by flow cytometry. Real-time PCR and western blotting were used to assess Wnt/β-catenin signaling, epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). Real-time cell analysis (RTCA) was used to detect the cell migration ability. After wnt-c59 treatment for 24 h, relative genes and transcriptional targets of Wnt/β-catenin signaling were downregulated (P<0.05). CCK-8 assay indicated that the combination of TSA and wnt-c59 had a synergistic effect on induction of Panc-1/TSA cell apoptosis. As detected by FACS, cell apoptosis rates increased significantly (P<0.05). The results of RTCA showed that the cell indices of the control group, wnt-c59 group, TSA group and TSA+wnt-c59 combination group were 1.2842±0.0257, 1.2155±0.0282, 1.2533±0.0194 and 0.8541±0.0250, respectively. In accordance, MMP-9 protein in the wnt-c59 treatment groups was decreased compared to the non-wnt-c59 treatment groups. Meanwhile, E-cadherin protein was upregulated and vimentin protein was downregulated, both of which are characteristic markers of EMT. Chemoresistant gene MDR1 and P-glycoprotein (P-gp) in the wnt-c59 treatment groups had a reduced expression compared to the non-wnt-c59 treatment groups. This study revealed that TSA sensitivity, migration ability, and the EMT phenotype in Panc-1/TSA cells were reversed following Wnt/β-catenin signaling inhibition.

/pdf/reversion-of-trichostatin-a-resistance-via-inhibition-of-the-4iszuip1fj.pdf

Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells

Objectives: Histone deacetylase inhibitors represent a promising class of potentialanticancer agents for the treatment of human malignancies. In this study, the effects oftrichostatin A (TSA) on apoptosis, metastasis-associated gene expression, and activation of theNotch pathway in human pancreatic cancer cell lines were investigated.Methods: After treatment with TSA, cell viability and apoptosis were evaluated using the MTT[3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide] assay, Hoechst 33258 staining, and flow cytometry. Moreover, RT-PCRand western blot analyses were performed to measure the expression levels of apoptosis-associated genes (Bcl-2, Bax, and caspase-3),metastasis-associated genes (E-cadherin, vimentin, and matrix metalloproteinases), and Notch pathway activation (Notch intracellulardomain, NICD). The levels of matrix metalloproteinase 2 and NICD were also semi-quantified by immunoassay.Results: Following treatment with TSA for 24 h, PANC-1, SW1990, and MIATACA-2 cells exhibited cell death. The MTT assayrevealed that TSA significantly decreased cell viability in a dose-dependent manner in PANC-1 cells. The Hoechst 33258 staining andflow cytometry results evidenced a significant increase in PANC-1 cell apoptosis following TSA treatment. The expression levels of Baxand caspase-3 were increased significantly, whereas Bcl-2 was down-regulated after TSA treatment. In the PANC-1 cells that survivedafter TSA treatment, the expression levels of vimentin, E-cadherin, and MMP genes were altered by the promotion of potential metastasisand increased expression of NICD.Conclusions: TSA can induce apoptosis of pancreatic cancer cells. In addition, the up-regulation of metastasis-related genes and theactivation of the Notch pathway in the survived PANC-1 cells may be associated with a too-low level of TSA or resistance to TSA.

Promotion of Metastasis-associated Gene Expression in Survived PANC-1 Cells Following Trichostatin A Treatment

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Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells

Promotion of Metastasis-associated Gene Expression in Survived PANC-1 Cells Following Trichostatin A Treatment