Hypothalamic Menin regulates systemic aging and cognitive decline

Leng, Lige; Yuan, Ziqi; Su, Xiao; Chen, Zhenlei; Yang, Shangchen; Chen, Meiqin; Zhuang, Kai; Lin, Hui-Kuan; Sun, Hao; Li, Huifang; Xue, Mei; Xu, Jun; Yan, Jingqi; Chen, Zhenyi; Yuan, Ti‐Fei; Zhang, Jie

doi:10.1371/journal.pbio.3002033

Cited by 13 publications

(4 citation statements)

References 43 publications

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“…Emerging studies have unveiled a role for the MEN1 gene and its protein product menin in regulating cytokine expression and driving cellular senescence [37–39]. Given that MEN1 DGASTs exhibit features of the senescence‐associated secretory phenotype, including cell cycle arrest (e.g.…”

Section: Discussionmentioning

confidence: 99%

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Duan,

Sawyer,

Witten

et al. 2024

The Journal of Pathology

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Gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor‐derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone‐secreting and non‐functional GEP‐NETs. By combining this approach with in vitro studies of human‐derived organoids, we demonstrated the convergence of cell autonomous immune and pro‐inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural‐ and immune‐related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal‐appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro‐inflammatory signaling was confirmed using patient‐derived duodenal organoids. Gastrin‐secreting and non‐functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non‐MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro‐inflammatory and pro‐neural factor IL‐17B. Treatment of human duodenal organoids with IL‐17B activated NF‐κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue‐specific neuro‐immune signatures in GEP‐NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro‐inflammatory factors, including tumor‐derived IL‐17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Duan,

Sawyer,

Witten

et al. 2024

The Journal of Pathology

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“…Cognitive ability not only forms the basis for the self-care capabilities of older people, it is also a crucial skill for enhancing their quality of life ( 16 , 17 ) and overall well-being ( 18 , 19 ). However, it is widely accepted that cognitive decline is inevitable with aging ( 20 ). Therefore, methods to mitigate or delay the age-related cognitive decline in older people are important for successful self-care and for China to effectively address depleting social resource due to an aging population.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal associations between the frequency of playing Mahjong and cognitive functioning among older people in China: evidence from CLHLS, 2008–2018

Zhu,

Wang,

et al. 2024

Front. Public Health

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BackgroundCognitive decline is prevalent among older adults, often resulting in decreased capabilities for self-care and a diminished quality of life. Mahjong, a culturally cherished and extensively played intellectual game in China, demands considerable cognitive function. While the cognitive benefits of playing Mahjong have been widely accepted, this study investigates an under explored aspect and aimed to ascertain the game’s potential contributions toward bolstering self-care abilities, enhancing overall quality of life, and mitigating against rising societal healthcare costs.MethodsThe data analyzed in the study is collected from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) with cognitive functioning being assessed through the Mini-Mental State Examination (MMSE). The frequency of playing Mahjong was measured through a self-reported questionnaire. Multiple linear regression models, latent variable growth models, and cross-lagged models were used to investigate the longitudinal relationship between game frequency and cognitive function in older people.ResultsOf the 7,535 participants, the mean (SD) age was 81.96 (10.53) years. There were 7,308 (97%), 4,453 (59%), and 1,974 (26%) participants in 2011, 2014, and 2018, respectively. The results showed that Mahjong players had significantly higher MMSE scores compared to non-players from 2008 to 2018 (β = 0.893; p < 0.001), and non-players had significantly lower scores in 2011, 2014, and 2018 than in 2008 (β = −1.326, −0.912, −0.833; Ps > 0.05). Moreover, the frequency of playing Mahjong was associated with improved various cognitive domains. The declining frequency of playing Mahjong was substantially associated with the declining rate of MMSE scores (r = 0.336; p < 0.001). Mahjong frequency showed positive effects on MMSE scores, while the influence of Mahjong on MMSE scores were not significant.ConclusionPlaying Mahjong has a positive influence on the cognitive functioning among older people. It can help buffer against the decline in cognitive function and maintain cognitive function levels. The higher frequency of playing Mahjong is associated with improved reaction, attention and calculation, and self-coordination. A decline in the frequency of playing Mahjong was associated with a declining rate of cognitive function. The higher frequency of playing Mahjong among older people unilaterally influenced the improvement of cognitive function levels in older people in China.

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“…However, our recent study demonstrates that MEN1-mediated alternative RNA splicing reprogramming also play an important role for its tumor suppressor activity; this aspect of MEN1 function believed to may be associated with ferroptosis rather than apoptosis 10 . Furthermore, there is evidence that MEN1 impacts the metabolism at least in part by regulating the expression of metabolic targets 11 , suggesting that MEN1-mediated metabolic regulation is crucially involved in repressing lung cancer development in vivo. Given the above, we sought to explore the biological signi cance and molecular mechanisms played by which MEN1 in regulating ferroptosis in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

MEN1-mediated CD44 alternative splicing depression is required for ferroptosis during lung cancer suppression

Bangming,

Pan,

Zhu

et al. 2024

Preprint

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Ferroptosis is a characteristic form of cell death triggered by excessive iron-dependent reactive oxygen species (ROS) and plays an important role in suppressing tumor development. Although MEN1-regulated cell-cycle arrest, apoptosis, and cell senescence have been considered foremost barriers to lung tumorigenesis, its other functions, such as RNA splicing regulation, are also important for its tumor suppression activity. Here, MEN1 was found to facilitate lipid ROS generation and sensitizes lung cancer cells to ferroptosis by depressing alternative CD44 pre-mRNA splicing. CD44 variant isoforms are highly expressed and correlated with poor prognosis in human lung cancers. Loss of Men1 profoundly accelerates the progression of Kras-mutant driven lung adenocarcinoma (LUAD), which is associated with the accumulation of CD44 variant isoforms found in a KrasG12D;Men1-specific deficient mouse model. Mechanistically, MEN1 maintains a relatively slow RNA polymerase II (Pol II) elongation by controlling the release of Pol II-associated factor 1 (PAF1) from the CD44 gene body, which in turn prevents the inclusion of CD44 variable exon (CD44v). Furthermore, CD44v6-interfering peptides effectively abrogate the growth and metastasis of established Kras-mutant LUAD and MEN1-deficient tumors by activating ferroptosis. The efficacy of CD44v6 peptides was stronger than that of erastin, a ferroptosis inducer, in MEN1-deficient tumors. Collectively, our study unveils a novel way of tumor suppression based on MEN1 regulation of CD44 alternative splicing, ROS production and ferroptosis.

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Hypothalamic Menin regulates systemic aging and cognitive decline

Cited by 13 publications

References 43 publications

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Longitudinal associations between the frequency of playing Mahjong and cognitive functioning among older people in China: evidence from CLHLS, 2008–2018

MEN1-mediated CD44 alternative splicing depression is required for ferroptosis during lung cancer suppression

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