5-Hydroxytryptamine receptors (5-HTRs) are strongly correlated with tumor progression in various types of cancer. Despite this, the underlying mechanisms responsible for the role of 5-HTRs in non-small cell lung cancer (NSCLC) remains unclear. This study aimed to investigate the relationship between 5-hydroxytryptamine receptor 3A (HTR3A) and NSCLC development. Our findings indicated a higher distribution of HTR3A expression in NSCLC tissues when compared with normal tissues, where patients with high HTR3A levels demonstrated shorter overall survival times. In vitro analyses revealed that overexpression of HTR3A facilitated the proliferation and migration of NSCLC cell lines (A549 and NCI-H3255). Similarly, a notable acceleration of tumor growth and enhanced pulmonary tumorigenic potential were observed in HTR3A-overexpressing tumor-bearing mice. Mechanistically, upregulation of Forkhead Box H1 (FOXH1) by HTR3A led to the activation of Wnt3A/β-catenin signaling pathways, thereby promoting the development of NSCLC. Our report thus highlights the significance of the HTR3A/FOXH1 axis during tumor progression in NSCLC, proposing HTR3A as a possible diagnostic indicator and candidate target for clinical therapy.

Mounting evidence in animal experiments proves that early life stage exposure to organophosphate flame retardants (OPFRs) affects the locomotor behavior and changes the transcriptions of central nervous system genes. Unfortunately, their effect on human motor neuron (MN) development, which is necessary for body locomotion and survival, has not yet characterized. Here, we utilized a spinal cord MN differentiation model from human embryonic stem cells (ESCs) and adopted this model to test the effects of two typical OPFRs tris (2-butoxyethyl) phosphate (TBEP) and tris (2-chloroethyl) phosphate (TCEP), on MN development and the possible mechanisms underlying. Our findings revealed TBEP exerted a much more inhibitory effect on MN survival, while TCEP exhibited a stronger stimulatory effect on ESCs differentiation into MN, and thus TBEP exhibited a stronger inhibition on MN development than TCEP. RNA sequencing analysis identified TBEP and TCEP inhibited MN survival mainly by disrupting extracellular matrix (ECM)-receptor interaction. Focusing on the pathway guided MN differentiation, we found both TBEP and TCEP activated BMP signaling, whereas TCEP simultaneously downregulated Wnt signaling. Collectively, this is the first study demonstrated TBEP and TCEP disrupted human MN development by affecting their survival and differentiation, thereby raising concern about their potential harm in causing MN disorders.

During vascular development, radial glial cells (RGCs) regulate vascular patterning in the trunk and contribute to the early differentiation of the blood-brain barrier. Ablation of RGCs results in excessive sprouting vessels or the absence of bilateral vertebral arteries. However, interactions of RGCs with later brain vascular networks after pattern formation remain unknown. Here, we generated a her4.3 transgenic line to label RGCs and applied the metronidazole/nitroreductase system to ablate her4.3+ RGCs. The ablation of her4.3+ RGCs led to the collapse of the cerebral vascular network, disruption of the blood-brain barrier, and downregulation of Wnt signaling. The inhibition of Wnt signaling resulted in the collapse of cerebral vasculature, similar to that caused by her4.3+ RGC ablation. The defects in the maintenance of brain vasculature resulting from the absence of her4.3+ RGCs were partially rescued by the activation of Wnt signaling or overexpression of Wnt7aa or Wnt7bb. Together, our study suggests that her4.3+ RGCs maintain the cerebral vascular network through Wnt signaling.

Posttraumatic stress disorder (PTSD) is a complex mental disorder notable for traumatic experience memory. Although current first-line treatments are linked with clinically important symptom reduction, a large proportion of patients retained to experience considerable residual symptoms, indicating pathogenic mechanism should be illustrated further. Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation. However, its role in PTSD remains to be elucidated. In this study, we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus. Fluoxetine, but not risperidone or sertraline, has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities. Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling. Our data demonstrated the correlation between PTSD and abnormal myelination, suggesting that the oligodendroglial lineage could be a target for PTSD treatment.

Autism spectrum disorder (ASD) is a group of neurodevelopment disorders characterized by deficits in social interaction and communication, and repetitive or stereotyped behavior. Autistic children are more likely to have vision problems, and ASD is unusually common among blind people. However, the mechanisms behind the vision disorders in autism are unclear. Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice. In this study, we investigated the relationship between vision abnormality and autism using an XAV939-induced mouse model of autism. We found that the mice receiving XAV939 had decreased amplitude of bright light-adaptive ERG. The amplitudes and latency of flash visual evoked potential recorded from XAV939-treated mice were lower and longer, respectively than in the control mice, suggesting that XAV939 inhibits visual signal processing and conductance. Anatomically, the diameters of RGC axons were reduced when Axin2 was stabilized during the development, and the optic fibers had defective myelin sheaths and reduced oligodendrocytes. The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

Breast cancer (BC) is the most common malignancy in women worldwide. Wnt signaling is involved in tumorigenesis and cancer progression, and is closely associated with the characteristics of BC. Variation in the expression of exosomal microRNAs (miRNAs) modulates key cancer phenotypes, such as cellular proliferation, epithelial‑mesenchymal transition, metastatic potential, immune evasion and treatment resistance. The present review aimed to discuss the importance of Wnt signaling and exosomal miRNAs in regulating the occurrence and development of BC. In addition, the present review determined the crosstalk between Wnt signaling and exosomal miRNAs, and highlighted potential diagnostic biomarkers and therapeutic targets.

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, e.g., Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in-depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.

The Wnt signaling pathway is a huge network governing development and homeostasis, dysregulation of which is associated with a myriad of human diseases. The Frizzled receptor (FZD) family comprises receptors for Wnt ligands, which indispensably mediate Wnt signaling jointly with a variety of co-receptors. Studies of FZDs have revealed that 10 FZD subtypes play diverse roles in physiological processes. At the same time, dysregulation of FZDs is also responsible for various diseases, in particular human cancers. Enormous attention has been paid to the molecular understanding and targeted therapy of FZDs in the past decade. In this review, we summarize the latest research on FZD structure, function, regulation and targeted therapy, providing a basis for guiding future research in this field.

Colorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (ApcMin/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.