Biology subjects

Xie, R.

Publications and source records attributed to Xie, R..

59 records · Page 4Linked to original sources

bioRxiv2020

Core Role of TRPC6 in Regulating Airway Re-modelling in Chronic Obstructive Pulmonary Disease

RationaleThe mechanistic role of canonical transient receptor potential 6 (TRPC6) channel in chronic obstructive pulmonary disease (COPD) is poorly understood. ObjectivesThe purpose of this study is to determine the role of TRPC6 channel in COPD and its underlying signaling mechanisms in human airway smooth muscle cells (HASMCs). Methods and Main ResultsThe present study examined the effects of TRPC6 channel on nicotine and cigarette induced HASMCs proliferation, migration and mouse airway remodeling models. mRNA and protein expression of TRPC6 were increased in cultured HASMCs incubated with nicotine using real-time PCR and western blot analysis. Nicotine treatment significantly increased TRPC6 transcriptional activity through NF-{kappa}B in HASMCs with Co-IP and electrophoretic mobility shift assays (EMSA). Nicotine treatment also increased ROS level in HASMCs, this increase was attenuated by Nox inhibitor apocynin. miR-135a/b-5p down-regulated mRNA and protein level of TRPC6 in HASMCs, while luciferase reporter assay showed that miR-135a/b-5p targeted at the 3-UTR of TRPC6 mRNA. microRNA-135a/b-5p (miR-135a/b-5p), with a negative correlation to TRPC6 expression, was low in airway smooth muscle of COPD patients. Cigarette-induced airway remodeling mice model also exhibited a large increase in smooth muscle cell proliferation and smooth muscle layer mass with immunohistochemistry assay, this well-characterized airway remodeling was eliminated by lentivirus of TRPC6 knockdown or miR-135a/b-5p overexpression. ConclusionsNicotine exposure results in increased HASMCs proliferation and migration through NF-{kappa}B signaling. Inhalation of cigarette causes airway smooth muscle layer re-modeling due to altered TRPC6 elicited Ca2+ influx, miR-135a/b-5p abolishes this change both in vitro and in vivo.

cell biology↗

bioRxiv2019

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/floxmice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.

cancer biology↗

bioRxiv2019

Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity

WW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain scaffold proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins such as {beta}-Dystroglycan, JCAD, and PTPN21. The WW tandem-mediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.

biophysics↗

bioRxiv2019

Classification of Neurons in the Adult Mouse Cochlear Nucleus: Linear Discriminant Analysis

The cochlear nucleus (CN) transforms the spike trains of spiral ganglion cells into a new set of sensory representations that are essential for auditory discriminations and perception. These transformations require the coordinated activity of different classes of neurons that are embryologically derived from distinct sets of precursors. Decades of investigation have shown that the neurons of the CN are differentiated by their ion channel expression and intrinsic excitability. In the present study we have used linear discriminant analysis (LDA) to perform an unbiased analysis of measures of the responses of CN neurons to current injections to mathematically separate cells on the basis of both morphology and physiology. Recordings were made from cells in brain slices from CBA mice and a transgenic mouse line, NF107, crossed against the Ai32 line. For each cell, responses to current injections were analyzed for spike rate, spike shape (action potential height, afterhyperpolarization depth, first spike half-width), input resistance, resting membrane potential, membrane time constant, hyperpolarization-activated sag and time constant. Cells were filled with dye for morphological classification, and visually classified according to published accounts. The different morphological classes of cells were separated with the LDA. Ventral cochlear nucleus (VCN) bushy cells, planar multipolar (T-stellate) cells, and radiate multipolar (D-stellate) cells were in separate clusters, and were also separated from all of the neurons from the dorsal cochlear nucleus (DCN). Within the DCN, the pyramidal cells and tuberculoventral cells were largely separated from a distinct clusters of cartwheel cells. DCN cells fell largely within a plane in the first 3 principal axes, whereas VCN cells were in 3 clouds approximately orthogonal to this plane. VCN neurons from the two mouse strains were slightly separated, indicating either a strain dependence or the differences in slice preparation methods. We conclude that cochlear nucleus neurons can be objectively distinguished based on their intrinsic electrical properties, but that such distinctions are still best aided by morphological identification.

neuroscience↗

bioRxiv2018

VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression

Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.

cancer biology↗