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Dysregulation of wingless‐type (Wnt) signaling is implicated in hepatocellular carcinoma (HCC). Wnt family member 8B (Wnt8B), one of the canonical Wnt ligands, is implicated in oncogenesis. However, the role of Wnt8B in human HCCs and its transcriptional regulation mechanism are presently unknown . Here, we report that Wnt8B expression was frequently increased in HCCs and was significantly associated with poorer patient prognosis. Wnt8B knockdown suppresses HCC cell growth both in vitro and in vivo via inhibiting the canonical Wnt signaling. Zinc finger transcription factor 191 (ZNF191) can positively regulate Wnt8B mRNA and protein expression, and promoter luciferase assay indicated that ZNF191 can increase the transcription activity of the 2‐Kbps WNT8B promoter. Chromatin immunoprecipitation‐qPCR and electrophoretic mobility shift assay showed that ZNF191 protein directly binds to the WNT8B promoter, and the binding sites are at nt‐1491(ATTAATT) and nt‐1178(ATTCATT). Moreover, Wnt8B contributes to the effect of ZNF191 on cell proliferation, and Wnt8B expression correlates positively with ZNF191 in human HCCs. Our findings suggested that Wnt8B, directly transcriptionally regulated by ZNF191, plays a pivotal role in HCC proliferation via the canonical Wnt pathway and may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients. Aberrant activation of the canonical wingless‐type (Wnt) signaling is involved in hepatocellular carcinoma (HCC). Here, we report Wnt8B, one of the canonical Wnt ligands, is upregulated in human HCCs and is significantly associated with poorer prognosis. Zinc finger transcription factor 191 (ZNF191) can directly bind to the WNT8B promoter and transactivate the WNT8B gene and subsequently activate the Wnt pathway to promote cell proliferation. Wnt8B expression correlates positively with ZNF191 in HCC specimens. Thus, Wnt8B may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients.

Wnts are highly-conserved lipid-modified secreted proteins that activate multiple signaling pathways. These pathways regulate crucial processes during various stages of development and maintain tissue homeostasis in adults. One of the most fascinating aspects of Wnt protein is that despite being hydrophobic, they are known to travel several cell distances in the extracellular space. Research on Wnts in the past four decades has identified several factors and uncovered mechanisms regulating their expression, secretion, and mode of extracellular travel. More recently, analyses on the importance of Wnt protein gradients in the growth and patterning of developing tissues have recognized the complex interplay of signaling mechanisms that help in maintaining tissue homeostasis. This review aims to present an overview of the evidence for the various modes of Wnt protein secretion and signaling and discuss mechanisms providing precision and robustness to the developing tissues.

Purpose of ReviewArthritis defines a large group of diseases primarily affecting the joint. It is the leading cause of pain and disability in adults. Osteoarthritis (OA) affecting the knee or hip is the most common form among over 100 types of arthritis. Other types of arthritis include erosive hand OA, temporomandibular joint (TMJ) OA, facet joint OA, diffuse idiopathic skeletal hyperostosis (DISH), and spondyloarthritis (SpA). However, the specific molecular signals involved in the development and progression of OA and related forms of arthritis remain largely unknown. The canonical wingless/integrated (Wnt)/β-catenin signaling pathway could play a unique role in the pathogenesis of arthritis. In this review article, we will focus on the molecular mechanisms of Wnt/β-catenin signaling in the pathogenesis of OA and other types of arthritis.Recent FindingsEmerging evidence demonstrates that Wnts and Wnt-related molecules are involved in arthritis development and progression in human genetic studies and in vitro studies. Also, mouse models have been generated to determine the role of Wnt/β-catenin signaling in the pathogenesis of arthritis.SummaryWnt/β-catenin signaling represents a unique signaling pathway regulating arthritis development and progression, and the molecules in this particular pathway may serve as targets for the therapeutic intervention of arthritis. Mediators and downstream effectors of Wnt/β-catenin signaling are increased in OA as well other forms of arthritis, including DISH and SpA. Through extensive investigations, including pre-clinical studies in transgenic mice and translational and human studies, the Wnt/β-catenin signaling pathway has been proven to play roles in bone and joint pathology by directly affecting bone, cartilage, and synovial tissue; further, these pathologies can be reduced through targeting this pathway. Continued investigation into the distinct molecular signaling of the Wnt/β-catenin pathway will provide additional insights toward the therapeutic intervention in arthritis.

Wings have provided an evolutionary advantage to insects and have allowed them to diversify. Here, we have identified in Drosophila a highly robust regulatory mechanism that ensures the specification and growth of the wing not only during normal development but also under stress conditions. We present evidence that a single wing-specific enhancer in the wingless gene is used in two consecutive developmental stages to first drive wing specification and then contribute to mediating the remarkable regenerative capacity of the developing wing upon injury. We identify two evolutionary conserved cis-regulatory modules within this enhancer that are utilized in a redundant manner to mediate these two activities through the use of distinct molecular mechanisms. Whereas Hedgehog and EGFR signalling regulate Wingless expression in early primordia, thus inducing wing specification from body wall precursors, JNK activation in injured tissues induce Wingless expression to promote compensatory proliferation. These results point to evolutionarily linked conservation of wing specification and regeneration to ensure robust development of the wing, perhaps the most relevant evolutionary novelty in insects. The wing is a remarkable evolutionary novelty in insects. Here the authors demonstrate that the specification and regenerative capacity of the wing relies on a single wing-specific enhancer of the wingless gene in Drosophila .

This review focuses on the osteogenic differentiation of mesenchymal stem cells (MSC), bone formation and turn-over in good and ill skeletal fates. The interacting molecular pathways which control bone remodeling in physiological conditions during a lifelong process are described. Then, alterations of the molecular pathways regulating osteogenesis are addressed. In the aging process, as well as in glucocorticoid-induced osteoporosis, bone loss is caused not only by an unbalanced bone resorption activity, but also by an impairment of MSCs’ commitment towards the osteogenic lineage, in favour of adipogenesis. Mutations affecting the expression of key genes involved in the control of bone development occur in several heritable bone disorders. A few examples are described in order to illustrate the pathological consequences of perturbation in different steps of osteogenic commitment, osteoblast maturation, and matrix mineralization, respectively. The involvement of abnormal MSC differentiation in cancer is then discussed. Finally, a brief overview of clinical applications of MSCs in bone regeneration and repair is presented.

This paper presents the development of a robust sizing method to efficiently estimate and compare key performance parameters in the conceptual design stage for the two main classes of fully electric vertical take-off and landing (eVTOL) aircraft, the powered lift and wingless aircraft types. The paper investigates hybrids of classical root-finding methods: the bisection, fixed-point and Newton-Rapson methods for use in eVTOL aircraft sizing. The improved convergence efficiency of the hybrid methods is at least 70% faster than the standard methods. This improved efficiency is significant for complex sizing problems. The developed sizing method is used to investigate the comparative performance of the wingless and powered lift eVTOL aircraft types for varying mission lengths. For a generic air taxi mission with a payload of 400 kg, the powered lift type demonstrates its mass efficiency when sized for missions above 10 km in range. However, the simpler architecture of the wingless eVTOL aircraft type makes it preferable for missions below 10 km in range when considering energy efficiency. The results of the sizing study were compared against a selection of eVTOL aircraft data. The results showed a good agreement between the estimated aircraft mass using the proposed sizing method and published eVTOL aircraft data.

The ability to regenerate following stress is a hallmark of self‐renewing tissues. However, little is known about how regeneration differs from homeostatic tissue maintenance. Here, we study the role and regulation of Wingless (Wg)/Wnt signalling during intestinal regeneration using the Drosophila adult midgut. We show that Wg is produced by the intestinal epithelial compartment upon damage or stress and it is exclusively required for intestinal stem cell (ISC) proliferation during tissue regeneration. Reducing Wg or downstream signalling components from the intestinal epithelium blocked tissue regeneration. Importantly, we demonstrate that Wg from the undifferentiated progenitor cell, the enteroblast, is required for Myc‐dependent ISC proliferation during regeneration. Similar to young regenerating tissues, ageing intestines required Wg and Myc for ISC hyperproliferation. Unexpectedly, our results demonstrate that epithelial but not mesenchymal Wg is essential for ISC proliferation in response to damage, while neither source of the ligand is solely responsible for ISC maintenance and tissue self‐renewal in unchallenged tissues. Therefore, fine‐tuning Wnt results in optimal balance between the ability to respond to stress without negatively affecting organismal viability. Studying molecular mechanisms of intestinal stem cell homeostasis in the Drosophila midgut, Cordero et al report a sole epithelial origin of Wingless during damage‐induced tissue regeneration.

Female mosquitoes require a blood meal for reproduction, and this blood meal provides the underlying mechanism for the spread of many important vector-borne diseases in humans. A deeper understanding of the molecular mechanisms linked to mosquito blood meal processes and reproductive events is of particular importance for devising innovative vector control strategies. We found that the conserved microRNA miR-8 is an essential regulator of mosquito reproductive events. Two strategies to inhibit miR-8 function in vivo were used for functional characterization: systemic antagomir depletion and spatiotemporal inhibition using the miRNA sponge transgenic method in combination with the yeast transcriptional activator gal4 protein/upstream activating sequence system. Depletion of miR-8 in the female mosquito results in defects related to egg development and deposition. We used a multialgorithm approach for miRNA target prediction in mosquito 3′ UTRs and experimentally verified secreted wingless-interacting molecule ( swim ) as an authentic target of miR-8. Our findings demonstrate that miR-8 controls the activity of the long-range Wingless (Wg) signaling by regulating Swim expression in the female fat body. We discovered that the miR-8/Wg axis is critical for the proper secretion of lipophorin and vitellogenin by the fat body and subsequent accumulation of these yolk protein precursors by developing oocytes. Significance Mosquitoes transmit some of the most devastating human diseases. Acquisition of blood initiates a cascade of events in various tissues in the female mosquito. Here we describe our study using newly established genetic tools in mosquito biology and a comprehensive microRNA target identification analysis to characterize microRNA-8 (miR-8) functionally in Aedes aegypti female mosquitoes. miR-8 works in the fat body by regulating its target, secreted wingless-interacting molecule . miR-8 acts on the long-range Wingless signaling pathway and plays an essential role in the female mosquito fat body controlling the secretory activity of yolk protein precursors required for oocyte development. Thus, this study identifies the fat body specific action of miR-8 and its target in regulating mosquito reproduction.

RING finger 43 (RNF43), a RING‐type E3 ubiquitin ligase, is a key regulator of WNT signaling and is mutated in 6–10% of pancreatic tumors. However, RNF43‐mediated effects remain unclear, as only a few in vivo substrates of RNF43 are identified. Here, it is found that RNF43‐mutated pancreatic cancer cells exhibit elevated B‐RAF/MEK activity and are highly sensitive to MEK inhibitors. The depletion of RNF43 in normal pancreatic ductal cells also enhances MEK activation, suggesting that it is a physiologically regulated process. It is confirmed that RNF43 ubiquitinates B‐RAF at K499 to promote proteasome‐dependent degradation, resulting in reduced MEK activity and proliferative ability in cancer cells. In addition, phosphorylation of B‐RAF at T491 suppresses B‐RAF ubiquitination by decreasing the interaction between RNF43 and B‐RAF. Mutations at K499 in B‐RAF are identified in various cancer types. MEK and WNT inhibitors synergistically suppress the growth of RNF43‐mutated pancreatic cancer cells in vitro and in vivo. Collectively, the research reveals a novel mechanism by which RNF43 inhibits B‐RAF/MEK signaling to suppress tumor growth and provide a new strategy for the treatment of RNF43‐inactivated pancreatic cancer. It is demonstrated that RNF43 ubiquitinates B‐RAF at K499, promoting its degradation. This ubiquitination process is negatively regulated by phosphorylation at T491. Inactivation of RNF43 enhances sensitivity to MEK inhibitors and creates synergy between drugs targeting the WNT and MEK pathways in various RNF43‐mutated cancers.

In Drosophila melanogaster, loss of regenerative capacity in wing imaginal discs coincides with an increase in systemic levels of the steroid hormone ecdysone, a key coordinator of their developmental progression. Regenerating discs release the relaxin hormone Dilp8 (Drosophila insulin-like peptide 8) to limit ecdysone synthesis and extend the regenerative period. Here, we describe how regenerating tissues produce a biphasic response to ecdysone levels: lower concentrations of ecdysone promote local and systemic regenerative signaling, whereas higher concentrations suppress regeneration through the expression of broad splice isoforms. Ecdysone also promotes the expression of wingless during both regeneration and normal development through a distinct regulatory pathway. This dual role for ecdysone explains how regeneration can still be completed successfully in dilp8⁻ mutant larvae: higher ecdysone levels increase the regenerative activity of tissues, allowing regeneration to reach completion in a shorter time. From these observations, we propose that ecdysone hormone signaling functions to coordinate regeneration with developmental progression.