1.Expression changes of inflammatory cytokines of tendon-derived stem cells in response to uniaxial stretching
Shengnan QIN ; Wen WANG ; Shiquan FU ; Yushan CHENG ; Qiming CHEN ; Honghui CHEN
Chinese Journal of Trauma 2015;31(3):269-272
Objective To observe the expression changes of inflammatory cytokines of human tendon-derived stem cells (TDSCs) under uniaxial stretching.Methods TDSCs were isolated from human gracilis tendon by collagenase digestion at very low density.Cells were detected for surface markers by flow cytometry,and tested for multi-differentiation potential in vitro.Repetitive uniaxial stretching was applied on the cells at 0%,4%,8% or 10% strain.Under the microscopy,cell alignment was observed after mechanical stretching.Expressions of inflammation factors COX-2 and MMP-1 were detected by qPCR and western blotting.Results TDSCs were successfully isolated from human gracilis tendon.Inflammatory cytokines CD29,CD44 and CD105 were positive,but CD45 and CD14 were negative.TDSCs could differentiate into osteocytes,adipocytes and chondrocytes in vitro.Cells were not realigned4 hours after mechanical stretching.MMP-1 mRNA expression was significantly down-regulated at 4% strain (0.090 ± 0.007) compared to that at 0% strain (0.247 ± 0.032,P < 0.05).No significant difference was found in COX-2 mRNA expression at 4% and 8% strain (both was 0.005 ±0.001,P >0.05).MMP-1 and COX-2 mRNA expressions at 8% strain (0.168 ± 0.040 and 0.007 ± 0.001)revealed no significant differences from those at 0% strain (0.134 ±0.075 and 0.006 ±0.003) (P >0.05),whereas at 10% strain MMP-1 and COX-2 mRNA expressions were significantly up-regulated (0.047 ± 0.003 and 0.496 ± 0.036) compared to those at 0% strain (0.011 ± 0.003 and 0.005 ± 0.003)(P < 0.05).Changes in MMP-1 and COX-2 protein expressions revealed similar trend as their mRNA expressions.In contrast to the setting of 0% strain,4% strain induced down-regulated MMP-1 and COX-2 proteins,8% strain induced no significant changes in MMP-1 and COX-2 proteins,and 10% strain induced up-regulated COX-2 protein despite minor increase in MMP-1 protein.Conclusions Mechanical stretching can affect the secretion of inflammatory cytokines.Low tensile stretch is associated with decreased expression of inflammatory cytokines while high tensile stretch promotes secretion of inflammatory cytokines.
2.Research on Remote-monitoring System for Patients Based on CDMA
Yubin ZHOU ; Feng WU ; Qiming CHENG ; Juan LIU ; Xinmin ZHANG ; Wei PAN ; Mengsun YU
Chinese Medical Equipment Journal 2003;0(10):-
Objective To design a wireless monitoring system which can obtain patients' multi-parameters (such as ECG, respiratory, blood pressure, SPO2, and heart rate). Methods The wireless communication system, based on CDMA, receives data through internet and analyses ECG by dealing and measuring signals. Results A wireless monitoring system is designed, which can analyse ECG, blood pressure, and respiratory. Doctors can give diagnostic suggestion based on the monitoring system's analyses and send it to patients by short messages. Conclusion This system can realize long -distance medical monitoring and report the diagnosis to patients timely.
3.Research of Portable Sleep Monitoring System
Feng WU ; Yubin ZHOU ; Qiming CHENG ; Xinmin ZHANG ; Wei PAN ; Juan LIU ; Mengsun YU
Chinese Medical Equipment Journal 2003;0(11):-
Objective To develop a portable sleep monitoring system with low burden. Methods Information from signals related with sleep were used and dug. Electrodes from patients' body were reduced to decrease patient's physiological and psychological burden. Results Polysomnography(PSG) is the gold standard in detecting the Sleep Apnea Hypopnea Syndrome disease at present. While this method has its problems, such as complicated operation, large expenditure and big physiology and psychology burden for the patient. A sleep monitor system was introduced which has the advantages of convenience, practicality, small physiology and psychology burden for the patient. Conclusion The result indicates that this device is warmly welcomed by doctors and patients, and it is a new device for the diagnosis of the SAHS disease.
4.Extraction of sleep structure information from heart rate variability based on spectrum analysis.
Feng WU ; Mengsun YU ; Qiming CHENG ; Zhangrui JIN ; Hongjin ZHANG
Journal of Biomedical Engineering 2004;21(2):212-214
In this study we made full use of the heart rate spectrum analysis to obtain the character parameters of heart rate variability related to EEG sleep phase information, and then we discarded the correlation between characteristics by employing Principal Component Analysis. Finally, by means of the decision tree based on Fisher rules, we established two full automatic models for identifying healthy people and sleep apnea hypopnea syndroma (SAHS) patients respectively. The result of experiments indicates that the model is accurate and robust.
Decision Trees
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Electrocardiography
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Electroencephalography
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Female
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Heart Rate
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physiology
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Humans
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Male
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Models, Biological
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Polysomnography
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Signal Processing, Computer-Assisted
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Sleep
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physiology
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Sleep Apnea Syndromes
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physiopathology
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Sleep Stages
5.Epidemiological survey on prevalence of alcohol dependence in Guangxi Zhuang Autonomous Region
Bo WEI ; Qiang CHENG ; Qiming FENG ; Runde PAN ; Qiuming CHENG ; Guoguang HUANG ; Zhenyu MA ; Li SU ; Zhenghua TANG ; Haining TANG ; Naying CHEN ; Faqin CHENG ; Huojia LI
Chinese Journal of Behavioral Medicine and Brain Science 2010;19(8):735-737
Objective To understand the prevalence of alcohol dependence in individuals living in Guangxi Zhuang Autonomous Region,China. Methods From July 2007 to December 2007,21290 subjects aged more than 15 were randomly selected for 6 Prefecture-level cities and 10 counties by stratified multi-stage cluster sampling method. All subjects were investigated by face to face interview. The Chinese version of Composite International Diagnostic Interview (CIDI3.0) Provided by the Chinese Center for Disease Control And Prevention was used as the screening tool and the diagnoses were made with the 10th edition of international classification of Disease Criteria. Results 18 219 subjects completed the screening,the Completion rate was 85.58‰. The general point prevalence and the general lifetime prevalence of alcohol dependence in individuals living in Guangxi was both 4.50‰. The general lifetime prevalence was higher in rural (6.17‰) than in urban (1.85‰) ( RR =0.31,95% CI =0. 17 ~0.57, P=0. 000) ,higher in men (8.59‰) than in women (0. 33‰) ( RR =0.04,95% CI =0. 01 ~ 0.13, P = 0.000 ) and higher in Zhuang (9.63‰) than in Han(1.95‰) ( RR = 5. 01,95% CI = 3.02 ~8.34, P = 0.000). The lifetime prevalence of alcohol dependence tends upwards as age increasing (P<0.05 ) and it differs in different marital status,higher in divorce groups (P < 0.05). Conclusion Schizophrenia, Depression disorder, Alcohol dependence disorder are the most common mental disorders and have become the public health problem in Guangxi. To do this,it is necessary to carry out targeted research in prevention and rehabilitation.
6.Clinical experience of surgical treatment in metastatic renal cell carcinoma with venous tumor thrombus
Zhuo LIU ; Xun ZHAO ; Guodong ZHU ; Shiying TANG ; Peng HONG ; Qiming ZHANG ; Liwei LI ; Shudong ZHANG ; Guoliang WANG ; Xiaojun TIAN ; Hongxian ZHANG ; Cheng LIU ; Lulin MA
Chinese Journal of Urology 2020;41(6):415-420
Objective:To investigate the safety and effectiveness of cytoreductive nephrectomy and tumor thrombectomy in patients with metastatic renal cancer with renal vein or inferior vena cava tumor thrombus.Methods:From February 2015 to May 2019, 56 cases of metastatic renal cell carcinoma with venous tumor thrombus were analyzed retrospectively, including 44 male (78.6%) and 12 female (21.4%)cases, and the average age was (59.2±10.7)(22-82). The clinical presentations covered local symptoms in 26 cases (46.4%), systemic symptoms in 8 cases (14.3%), both local symptoms and systemic symptoms in 12 cases (21.4%), and asymptomatic in 10 cases (17.9%). Among them, renal tumors were located in 35 cases (62.5%) on the right and 21 cases (37.5%) on the left. The average tumor diameter was (10.1±3.8)(1.5-21.1) cm. Forty-five cases (80.4%) scored 2 points and 11 cases (19.6%) scored 3 points by the American Society of anesthesiologists(ASA). Preoperative hemoglobin was (118.2±23.1)(72-178) g/L, and albumin was (37.9±5.6)(23-50) g/L, total protein was (67.7±6.7)(43-81) g/L, serum creatinine was (111.3±119.6)(32-958) μmol/L. There were 16 cases of Mayo 0 (28.6%), 14 cases of Mayo Ⅰ(25.0%), 17 cases of Mayo Ⅱ(30.4%), 4 cases of Mayo Ⅲ(7.1%), and 5 cases of Mayo Ⅳ(8.9%). Fourteen cases (25.0%) were in the stage of cN 0 and 42 cases (75.0%) in the stage of cN 1. Five cases (8.9%) had simple bone metastasis, 16 cases (28.6%) had simple lung metastasis, 2 cases (3.6%) had simple adrenal metastasis, 6 cases (10.7%) had simple liver metastasis, and 27 cases (48.2%) had 2 or more multiple system metastasis. According to the location of the organ system, 91 metastatic lesions were found in 56 patients. Among them, 37 cases (40.7%) had lung metastasis, 18 cases (19.8%) had liver metastasis, 21 cases (23.1%) had bone metastasis and 15 cases (16.5%) had adrenal metastasis. All 56 patients belonged to IMDC prognosis score model medium risk group. The surgical treatment of Mayo grade 0 tumor thrombus was the same as that of routine radical nephrectomy. The tumor thrombus of Mayo grade Ⅰ was removed after IVC was partially blocked by Satinsky′s forceps. The Mayo Ⅱ tumor thrombus was removed, after blocking the distal vena cava, the contralateral renal vein and the proximal vena cava. Mayo grade Ⅲ tumor thrombus needed pringer's method to block the first porta hepatis. For grade Ⅳ tumor thrombus the diaphragm could be cut directly, or the thrombus could be removed by cardiopulmonary bypass. Laparoscopic surgery was performed in 22 cases (39.3%) and open surgery in 30 cases (53.6%). Six cases (10.7%) underwent IVC wall resection because of tumor invasion. 32 cases (57.1%) underwent ipsilateral adrenalectomy because of tumor invasion or adrenal metastasis, and 23 cases (41.1%) underwent ipsilateral lymphadenectomy. In this study, there were 11 cases of solitary metastasis, 8 cases of which were operated on and 3 cases of which were not operated on. Forty-three patients were treated with sunitinib after palliative nephrectomy, 9 patients were treated with pazopanib, 3 patients were treated with acitinib, and 1 patient was treated with sorafenib. Results:The operations were successfully completed in 56 patients. Four cases (7.1%) changed from laparoscopic surgery to open surgery. The operation time was (326.8±114.9)(108-589) min. Intraoperative hemorrhage was (1 435.2±1 513.4)(20-6 000) ml, intraoperative red blood cells transfusion was (1 456.7±832.8)(400-3 600) ml in 30 cases, and intraoperative plasma transfusion was (700.0±473.6)(200-1 800) ml in 15 cases. The postoperative hospital stay was (10.6±4.6)(5-26) days. The serum creatinine one week after operation was (109.5±98.7) (47-772) μmol/L. There were 46 cases (82.1%) of renal clear cell carcinoma, 7 cases (12.5%) of papillary renal cell carcinoma and 3 cases (5.4%) of unclassified renal cell carcinoma. One case was WHO/ISUP 2016 nuclear grade 1 (1.8%), 20 cases(36.4%) was grade 2, 18 cases(32.7%)was grade 3, and 16 cases(29.1%)was grade 4. Early postoperative complications occurred in 22 cases (39.3%). Among them, 1 case of Clavien gradeⅠ was wound infection. There were 16 cases with Clavien gradeⅡ, including 5 cases who received blood transfusion due to anemia, 3 cases with chylous fistula, 4 cases with postoperative pulmonary infection, 2 cases with postoperative lower extremity venous thrombosis, 1 case with atrial fibrillation and 1 case with epididymitis. Clavien gradeⅢ a was found in 1 case with pneumothorax. Clavien gradeⅣ was found in 2 cases, including 1 case of acute cerebral infarction and 1 case of renal insufficiency.There were 2 cases with Clavien gradeⅤ with perioperative death. Among the 56 patients, 5 lost the follow-up, 2 died during the perioperative period, and the other 49 patients were followed up for 1-39 months, with a median follow-up of 14 months. The mean survival time was (25.6±2.5) months, and the median survival time was 25 months.Conclusions:It was relatively safe and effective to perform cytoreductive nephrectomy and tumor thrombectomy in patients with metastatic renal cancer with tumor thrombus. For the patients with clinical symptoms, IMDC prognosis score model medium risk group, and strong desire for surgery, the combination of cytoreductive nephrectomy with tumor thrombectomy and postoperative targeted medical therapy was recommended.
7.Effects of docetaxel for postoperative chemotherapy of advanced gastric cancer based on propensity score matching
Huan HU ; Shiyao WANG ; Guoqiang ZHANG ; Yanxian REN ; Qiming LEI ; Zhibin CHENG
Chinese Journal of Digestive Surgery 2020;19(11):1196-1204
Objective:To investigate the effects of docetaxel for postoperative chemotherapy of advanced gastric cancer.Methods:The propensity score matching and retrospective cohort study was conducted. The clinicopathological data of 311 patients with advanced gastric cancer who were admitted to Lanzhou University Second Hospital from January 2013 to December 2018 were collected. There were 224 males and 87 females, aged from 26 to 82 years, with a median age of 58 years. Of 311 patients, 204 cases undergoing chemotherapy with the FOLFOX regimen (oxaliplatin, calcium folinate, 5-fluorouracil) were allocated into the FOLFOX group, and 107 cases undergoing chemotherapy with the FLOT regimen (docetaxel, oxaliplatin, calcium folinate, 5-fluorouracil) were allocated into the FLOT group. Observation indicators: (1) the propensity score matching conditions and comparison of general data between the two groups of patients after matching; (2) follow-up; (3) analysis of survival factors; (4) subgroup analysis; (5) adverse reactions. Follow-up was performed using a combination of outpatient examination, hospitalization review and telephone interview to detect situations of patients chemotherapy, postoperative survival, tumor recurrence and metastasis up to February 2019. The propensity score matching was realized using the nearest neighbor method with 1: 1 ratio and caliper setting as 0.02. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Count data were described as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test or Fisher exact probability method. Rank data was analyzed using non parametric Rank sum test. The survival curve and rate were respectively drawn and calculated using the Kaplan-Meier method. The survival analysis was done using the Log-rank test. Univariate analysis and multivariate analysis were conducted using the COX regression model. Subgroup analysis was done using interaction test. Results:(1) The propensity score matching conditions and comparison of general data between the two groups of patients after matching: 198 of 311 patients had successful matching, including 99 in each group. Cases with tumor differentiated as poorly differentiation or well differentiation, cases with CA19-9 <27 U/mL or ≥27 U/mL, cases with CA125 <35 U/mL or ≥35 U/mL before propensity score matching were 109, 95, 156, 48, 186, 18 in the FOLFOX group, and 42, 65, 93, 14, 104, 3 in the FLOT group, respectively, showing significant differences in the above indicators between the two groups ( χ2=5.649, 4.798, 4.039, P<0.05). After propensity score matching, the above indicators were 44, 55, 85, 14, 96, 3 in the FOLFOX group, and 42, 57, 85, 14, 96, 3 in the FLOT group, respectively, showing no significant difference in the above indicators between the two groups ( χ2=0.082, 0.000, 0.000, P>0.05). (2) Follow-up: 198 patients of the two groups after matching were followed up for 2 to 69 months, with a median follow-up time of 38 months. During the follow-up, 92 cases survived without tumor, 2 cases underwent tumor recurrence or metastasis, and 104 cases died including 103 with tumor related death and 1 case with non-tumor related death. The courses of chemotherapy were 5.6±0.7 and 5.4±0.8 for the FOLFOX group and FLOT group, respectively, showing no significant difference between the two groups ( t=1.651, P>0.05). The 1, 3, and 5-year cumulative survival rates of patients were 72.2%, 31.5%, 27.7% and 83.2%, 42.8%, 38.2% for the FOLFOX group and FLOT group, respectively. The median overall survival time were 21 months and 34 months for the FOLFOX group and FLOT group, respectively, showing significant difference between the two groups ( χ2=4.473, P<0.05). (3) Analysis of survival factors: results of univariate analysis showed that cases undergoing chemotherapy with the FLOT regimen, cases with tumor as diffuse type of Lauren classification, cases with tumor as mixed type of Lauren classification, cases with tumor differentiated as well differentiation, cases with tumor diameter≥5 cm, cases with CA19-9≥27 U/mL, cases with carcinoembryonic antigen (CEA)≥3.4 μg/L, cases with tumor as T4 stage of T staging, cases with tumor as N2 stage of N staging, cases with tumor as N3 stage of N staging, cases undergoing distal gastrectomy and cases undergoing total gastrectomy were related factors influencing postoperative survival of patients ( hazard ratio=0.659, 1.617, 1.798, 0.672, 1.726, 1.655, 1.942, 2.036, 2.536, 4.085, 1.810, 2.310, 95% confidence interval: 0.444-0.978, 1.024-2.556, 1.105-2.926, 0.457-0.990, 1.159-2.569, 1.006-2.723, 1.295-2.912, 1.190-3.484, 1.409-4.564, 2.491-6.697, 1.020-3.211, 1.261-4.233, P<0.05). Results of multivariate analysis showed that cases undergoing chemotherapy with the FLOT regimen, cases with CEA≥3.4 μg/L, cases with tumor as N2 stage of N staging and cases with tumor as N3 stage of N staging were independent risk factors influencing postoperative survival of patients ( hazard ratio=0.622, 1.732, 2.217, 4.039, 95% confidence interval: 0.418-0.926, 1.124-2.670, 1.200-4.097, 2.448-6.662, P<0.05). (4) Subgroup analysis: results of subgroup analysis showed that of the different subgroups using gender, age, tumor Lauren classification, tumor differentiation degree, tumor location, tumor diameter, tumor markers, tumor T staging, tumor N staging and surgical procedures as subgrouping index, the efficacy difference between the FLOT group and the FOLFOX group was the same (interaction P>0.05). (5) Adverse reactions: the incidence of grade Ⅲ-Ⅳ adverse reactions of leukopenia, anemia, thrombocytopenia, nausea, vomiting and liver and kidney dysfunction were 11.1%(11/99), 2.0%(2/99), 3.0%(3/99), 12.1%(12/99), 4.0%(4/99), 1.0%(1/99) and 34.3%(34/99), 1.0%(1/99), 9.1%(9/99), 24.2%(24/99), 4.0%(4/99), 0 in the FOLFOX group and the FLOT group, respectively. There were significant differences of the incidence of leukopenia and nausea between the two groups ( χ2=15.213, 4.889, P<0.05). There was no significant difference of the incidence of thrombocytopenia between the two groups ( χ2=3.194, P>0.05) and there was no significant difference of the incidence of anemia, vomiting and liver and kidney dysfunction between the two groups ( P>0.05). There was no patient in the two group withdrawal from chemotherapy as no tolerance to toxic reactions. All patients were treated with glucocorticoids, proton pump inhibitors and serotonin receptor antagonists during chemotherapy. Patients undergoing leukopenia were treated with granulocyte stimulating factor. Conclusions:Compared with FOLFOX regimen, FLOT regimen which adds docetaxel significantly prolongs the postoperative median overall survival time of patients with advanced gastric cancer. However, FLOT regimen increases the incidence of grade Ⅲ-Ⅳ adverse reactions of leukopenia and nausea.
8.Study on Improvement Effect and Mechanism of MEBO on LPS-induced Injury of Rat Skin Fibroblasts
Yan JIANG ; Qiming GONG ; Cheng WEI ; Feiyan LU ; Chenyi ZHUO ; Qianli TANG
China Pharmacy 2021;32(6):702-708
OBJECTIVE:To study the improvement effect and mechanism of MEBO on lipopolysaccharide (LPS)-induced injury of rat skin fibroblasts. METHODS :Skin fibroblasts of rats were divided into control group ,LPS group (5 μg/mL), Kangfuxin solution group (positive control ,5 μg/mL LPS+1.25% Kangfuxin solution )and MEBO group (5 μg/mL LPS+0.6 mg/mL MEBO),with 6 wells in each group. Inflammatory injury cell model was induced by LPS (except for control group ). After a certain period of cultivation ,the cell survival rate and cell migration rate were detected in each group. The contents of TNF-α and IL-6 in cell supernatant was detected. The localization and fluorescence intensity of IL- 6 protein were detected. The protein expression of PTEN ,p-p65,TNF-α,IL-6,PI3K and Akt in the fibroblasts were also determined. RESULTS :Compared with control group ,survival rate of the fibroblasts was increased significantly in LPS group ,while cell migration was decreased significantly;the contents of TNF-α and IL-6 in cell supernatant as well as relative protein expression of PTEN ,p-p65,TNF-α, IL-6 and PI 3K were increased significantly (P<0.05 or P<0.01);IL-6 protein mainly expressed in the cytoplasm ,and the fluorescence intensity was enhanced. Compared with LPS group ,survival rate of the fibroblasts was decreased significantly in Kangfuxin solution group and MEBO group ,while migration rate was increased significantly ;the contents of TNF-α and IL-6, relative protein expression of PTEN ,p-p65,TNF-α,IL-6(except for Kangfuxin solution group ),PI3K and Akt (except for Kangfuxin solution group ) were decreased significantly (P<0.05 or P<0.01),while fluorescence intensity of IL- 6 protein decreased;relative protein expression of TNF-α,IL-6,PI3K and Akt in MEBO group were significantly lower than Kangfuxin solution group (P<0.05 or P<0.01). CONCLUSIONS :MEBO can inhibit the proliferation of LPS-induced skin fibroblasts , reduce the level of inflammatory factors and the intensity of inflammatory reaction , which may be related to the jiang- down-regulation of PTEN/NF-κB,PI3K/Akt signaling pathway.
9.Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202).
Jianhua SHI ; Ying CHENG ; Qiming WANG ; Kai LI ; Lin WU ; Baohui HAN ; Gongyan CHEN ; Jianxing HE ; Jie WANG ; Haifeng QIN ; Xiaoling LI
Frontiers of Medicine 2022;16(5):766-772
Patients with small-cell lung cancer (SCLC) relapse within months after completing previous therapies. This study aimed to investigate the efficacy and safety of anlotinib as third- or further-line therapy in patients with short-term relapsed SCLC from ALTER1202. Patients with short-term relapsed SCLC (disease progression within 3 months after completing ⩾ two lines of chemotherapy) in the anlotinib (n = 67) and placebo (n = 34) groups were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, objective response rate (ORR), disease control rate, and safety. Anlotinib significantly improved median PFS/OS (4.0 vs. 0.7 months, P < 0.0001)/(7.3 vs. 4.4 months, P = 0.006) compared with placebo. The ORR was 4.5%/2.9% in the anlotinib/placebo group (P = 1.000). The DCR in the anlotinib group was higher than that in the placebo group (73.1% vs. 11.8%, P < 0.001). The most common adverse events (AEs) were hypertension (38.8%), loss of appetite (28.4%), and fatigue (22.4%) in the anlotinib group and gammaglutamyl transpeptidase elevation (20.6%) in the placebo group. No grade 5 AEs occurred. For patients with short-term relapsed SCLC, third- or further-line anlotinib treatment was associated with improved survival benefit. Further studies are warranted in this regard.
Humans
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Lung Neoplasms/drug therapy*
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Treatment Outcome
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Neoplasm Recurrence, Local/chemically induced*
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Quinolines/adverse effects*
10.LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells.
Zhen SUN ; Hua YU ; Jing ZHAO ; Tianyu TAN ; Hongru PAN ; Yuqing ZHU ; Lang CHEN ; Cheng ZHANG ; Li ZHANG ; Anhua LEI ; Yuyan XU ; Xianju BI ; Xin HUANG ; Bo GAO ; Longfei WANG ; Cristina CORREIA ; Ming CHEN ; Qiming SUN ; Yu FENG ; Li SHEN ; Hao WU ; Jianlong WANG ; Xiaohua SHEN ; George Q DALEY ; Hu LI ; Jin ZHANG
Protein & Cell 2022;13(7):490-512
LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.
Animals
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Cell Differentiation
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Embryo, Mammalian/metabolism*
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Embryonic Development
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Mice
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Pluripotent Stem Cells/metabolism*
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RNA, Messenger/genetics*
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RNA, Ribosomal
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RNA-Binding Proteins/metabolism*
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Transcription Factors/metabolism*
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Zygote/metabolism*