Browsing by Subject "Neuropeptides"

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Open Access
Prognostic biomarker identification and classification of colorectal cancer patients: a dual gene-based and sample-based approach
(2023-08) Naeemaee, Ronak
Colorectal cancer (CRC) is one of the most heterogeneous cancer types, with high mortality rates making it the one of the deadliest cancer among men and women. The heterogeneity of CRC comes from the numerous clinicopathological characteristics of these tumors, including; KRAS/BRAF mutation, Microsatellite Instability (MSI), and stage. Another essential factor recently emphasized is the tumor location (proximal or distal). Consequently, many studies have focused on finding prognostic biomarkers for CRC patients to increase the efficiency of their treatment plans. However, despite the attempts, these biomarkers fail in clinical transition as they lack robustness and consistent results in their validation studies. Moreover, understanding the mechanism behind CRC progression can significantly help the personalization of treatments. Recently, the cancer neuroscience field has been focusing on elucidating neuropeptides' role in cancer and CRC as they have been proven to be involved in cancer progression. Accordingly, the thesis was divided into two approaches. The first approach was to further examine the role of neuropeptides by finding a subset of neuropeptides for the classification of the CRC samples and following functional analysis to understand the mechanism of their involvement. Moreover, the second approach attempted the determination of robust prognostic biomarkers in a specific sample group (Proximal, Stages 2 and 3) while controlling for the inconsistencies. In the first approach, a subset of 9 neuropeptide genes was found through Principle Component Analysis (PCA) with the ability to stratify the CRC samples into high and low expression groups. Functional analyses of these groups identified an association between the up-regulation of these neuropeptides and Hedgehog's (HHG) signaling pathway, and these activities are hypothesized to be primarily specific to the stroma of the tumor. Up-regulation of these neuropeptides was also linked with other pathways involved in cancer progression, such as; EMT, angiogenesis, and TGFβ activities. The second approach utilized a new methodology pipeline that aimed to ensure the selection of genes with no discrepancies among their probesets and across different technologies. Following the pipeline, 3 genes were identified, associated with favorable and non-favorable prognoses for Proximal, Stage 2, and 3 samples. However, although a very stringent methodology was used and various clinicopathological parameters such as the stage and location were considered, the prognostic associations observed were not as consistent, indicating the importance of the sample's molecular characteristics. This study also pointed out potential implications of neuropeptides in CRC progression and development. More elaborative studies are required for the clarification of the interactions of neuropeptides with the HHG signaling pathway. Furthermore, the identified prognostic biomarkers need to be validated through comprehensive validation studies in their associating subgroups of samples, as they are robust biomarkers with the potential to be used in clinics.
Open Access
Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes α7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons
(2009) Hruska, M.; Keefe J.; Wert, D.; Tekinay, A.B.; Hulce J.J.; Ibañez-Tallon I.; Nishi, R.
Vertebrate α-bungarotoxin-like molecules of the Ly-6 superfamily have been implicated as balancers of activity and survival in the adult nervous system. To determine whether a member of this family could be involved in the development of the avian ciliary ganglion, we identified 6 Gallus genes by their homology in structure to mouse lynx1 and lynx2. One of these genes, an ortholog of prostate stem cell antigen (psca), is barely detectable at embryonic day (E) 8, before neuronal cell loss in the ciliary ganglion, but increases > 100-fold as the number of neurons begins to decline between E9 and E14. PSCA is highly expressed in chicken and mouse telencephalon and peripheral ganglia and correlates with expression of α7-containing nicotinic acetylcholine receptors (α7-nAChRs). Misexpressing PSCA before cell death in the ciliary ganglion blocks α7-nAChR activation by nicotine and rescues the choroid subpopulation from dying. Thus, PSCA, a molecule previously identified as a marker of prostate cancer, is a member of the Ly-6 neurotoxin-like family in the nervous system, and is likely to play a role as a modulator of α7 signaling-induced cell death during development. Copyright © 2009 Society for Neuroscience.
Open Access
A role for LYNX2 in anxiety-related behavior
(2009) Tekinay, A.B.; Nong, Y.; Miwa J.M.; Lieberam I.; Ibanez-Tallon I.; Greengard P.; Heintz, N.
Anxiety disorders are the most prevalent mental disorders in developed societies. Although roles for the prefrontal cortex, amygdala, hippocampus and mediodorsal thalamus in anxiety disorders are well documented, molecular mechanisms contributing to the functions of these structures are poorly understood. Here we report that deletion of Lynx2, a mammalian prototoxin gene that is expressed at high levels in anxiety associated brain areas, results in elevated anxiety-like behaviors. We show that LYNX2 can bind to and modulate neuronal nicotinic receptors, and that loss of Lynx2 alters the actions of nicotine on glutamatergic signaling in the prefrontal cortex. Our data identify Lynx2 as an important component of the molecular mechanisms that control anxiety, and suggest that altered glutamatergic signaling in the prefrontal cortex of Lynx2 mutant mice contributes to increased anxiety-related behaviors.