Structural basis for Y2 receptor-mediated neuropeptide Y and peptide YY signaling.

Abstract Both osteoporosis and depression are major health threats, but their interrelationship is not clear. This study elucidated the associations between osteoporosis and depression while considering the temporal sequence of the diagnoses. In this cross-sectional study, data were extracted from the Korean National Health and Nutrition Examination Surveys (2007–2009 and 2015–2019, n = 29,045). Osteoporosis and depression were defined by diagnoses thereof. The odds ratio (OR) of the incident osteoporosis among depression patients without a history of osteoporosis was calculated by multivariable logistic regression adjusted for potential confounders. A reverse association was also assessed. Participants were additionally stratified by their sex and age. As a result, male depression patients aged under 50 years showed higher ORs for osteoporosis than those without depression (OR 9.16, 95% CI 1.78–47.18). Female osteoporosis patients showed lower ORs for depression than those without osteoporosis (OR 0.71, 95% CI 0.58–0.88), especially in women aged 50 years and older. In the sensitivity analysis, the same results were obtained in women by their menopause status. Depression has a strong positive association with the occurrence of osteoporosis in young male adults, and osteoporosis has a negative association with the occurrence of depression in female adults. 

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Sex-specific bi‑directional association between osteoporosis and depression from the national representative data of South Korea

Epidermal growth factor receptor 2 (ERBB2) is commonly over-expressed in advanced or metastatic tissues of papillary thyroid cancer (PTC) with poor prognosis, while it remains unknown whether ERBB2 plays a role in the progression of PTC. Thus, we analyzed the data derived from online repositories, including TCGA, KEGG, GO, GeneMANIA, and STRING, to explore the relationship between ERBB2 expression and prognosis, tumor phenotypes of interest, and immune infiltrates in PTC. Compared to normal thyroid tissue, ERBB2 was up-regulated in PTC samples (p < 0.001); In comparison with the group with low expression of ERBB2, the group with high expression of ERBB2 had poorer progression-free interval in stage III/IV patients (p = 0.008) and patients aged >45 years (p = 0.019). The up-regulated ERBB2 was associated with iodine metabolism dysfunction, proliferation, metastasis, angiogenesis, and drug resistance. The expression of ERBB2 negatively correlated with enrichment scores of B cells (r = −0.176, p < 0.001), CD8+ T cells (r = −0.160, p < 0.001), cytotoxic cells (r = −0.219, p < 0.001), NK CD56dim cells (r = −0.218, p < 0.001), plasmacytoid dendritic cells (r = −0.267, p < 0.001), T cells (r = −0.164, p < 0.001), T follicular helper cells (r = −0.111, p = 0.012), gamma delta T cells (r = −0.105, p = 0.017), and regulatory T cells (r = −0.125, p = 0.005). In conclusion, ERBB2 may serve as a prognostic biomarker and an immunotherapeutic target in PTC, deserving further exploration.

https://www.frontiersin.org/articles/10.3389/fgene.2022.966365/pdf

ERBB2 as a prognostic biomarker correlates with immune infiltrates in papillary thyroid cancer

Membrane receptor clustering is fundamental to cell-cell communication; however, the physiological function of receptor clustering in cell signaling remains enigmatic. Here, we developed a dynamic platform to induce cluster formation of neuropeptide Y2 hormone receptors (Y2R) in situ by a chelator nanotool. The multivalent interaction enabled a dynamic exchange of histidine-tagged Y2R within the clusters. Fast Y2R enrichment in clustered areas triggered ligand-independent signaling as determined by an increase in cytosolic calcium and cell migration. Notably, the calcium and motility response to ligand-induced activation was amplified in preclustered cells, suggesting a key role of receptor clustering in sensitizing the dose response to lower ligand concentrations. Ligand-independent versus ligand-induced signaling differed in the binding of arrestin-3 as a downstream effector, which was recruited to the clusters only in the presence of the ligand. This approach allows in situ receptor clustering, raising the possibility to explore different receptor activation modalities. 

https://pubs.acs.org/doi/pdf/10.1021/acs.nanolett.2c03506

Dynamic <i>in Situ</i> Confinement Triggers Ligand-Free Neuropeptide Receptor Signaling

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system’s high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.

Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies

Breast cancer and osteoporosis are common diseases that affect the survival and quality of life in postmenopausal women. Women with breast cancer are more likely to develop osteoporosis than women without breast cancer due to certain factors that can affect both diseases simultaneously. For instance, estrogen and the receptor activator of nuclear factor-κB ligand (RANKL) play important roles in the occurrence and development of these two diseases. Moreover, chemotherapy and hormone therapy administered to breast cancer patients also increase the incidence of osteoporosis, and in recent years, neuropeptide Y (NPY) has also been found to impact breast cancer and osteoporosis.Y1 and Y5 receptors are highly expressed in breast cancer, and Y1 and Y2 receptors affect osteogenic response, thus potentially highlighting a potential new direction for treatment strategies. In this paper, the relationship between breast cancer and osteoporosis, the influence of NPY on both diseases, and the recent progress in the research and treatment of these diseases are reviewed.

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Yi-Zhong Li

Papers

Update on the Role of Neuropeptide Y and Other Related Factors in Breast Cancer and Osteoporosis