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Two missense stk11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1532-1546页

作者： Jin Liu Si-Cong Zeng An Wang Hai-Ying Cheng Qian-Jun Zhang Guang-Xiu Lu Hunan Guangxiu Hospital Hunan Normal UniversityChangsha 410000Hunan ProvinceChina Scientific Research Department Reproductive and Genetic Hospital of Citic-XiangyaChangsha 410000Hunan ProvinceChina

BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(stk11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.Pstk11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense stk11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our find

关键词： Missense stk11 Peutz-Jeghers syndrome Rare disease Genetic counseling Assisted reproductive technique

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A novel stk11 gene mutation (c.388dupG,p.Glu130Glyfs∗33) in a Peutz-Jeghers family and evidence of higher gastric cancer susceptibility associated with alterations in stk11 region aa 107-170

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Genes & Diseases 2022年第2期9卷 288-291页

作者： Giovanna Forte Filomena Cariola Katia De Marco Andrea Manghisi Filomena Anna Guglielmi Raffaele Armentano Giuseppe Lippolis Pietro Giorgio Cristiano Simone Vittoria Disciglio Medical Genetics National Institute of Gastroenterology“S.de Bellis”Research HospitalCastellana GrotteBari 70013Italy Histopathology Unit National Institute of Gastroenterology“S.de Bellis”Research HospitalCastellana GrotteBari 70013Italy Department of General Surgery National Institute of Gastroenterology“S.de Bellis”Research HospitalCastellana GrotteBari 70013Italy Gastroenterology and Digestive Endoscopy Unit National Institute of Gastroenterology“S.de Bellis”Research HospitalCastellana GrotteBari 70013Italy Department of Biomedical Sciences and Human Oncology(DIMO) Medical GeneticsUniversity of Bari Aldo MoroPiazza Umberto IBari 70124Italy

Peutz-Jeghers syndrome(PJS)is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation and gastrointestinal(GI)hamartomatous polyposis and is associated with an increased risk of gastrointestinal,breast,gynecologic and other extra-GI malignancies.The serine/threonine kinase 11(stk11)gene has been identi-fied as a pathogenic factor in PJS.stk11 is a tumor sup-pressor gene located on chromosome 19p13.3 and includes 9 coding exons.1 The stk11 protein is composed of 433 amino acids(aa)and comprises a kinase catalytic region(aa 49e309)as well as N-and C-terminal regulatory domains.

关键词： stk11 Jeghers alterations

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Peutz-Jeghers syndrome without stk11 mutation may correlate with less severe clinical manifestations in Chinese patients

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World Journal of Gastroenterology 2023年第21期29卷 3302-3317页

作者： Li-Xin Jiang Yu-Rui Chen Zu-Xin Xu Yu-Hui Zhang Zhi Zhang Peng-Fei Yu Zhi-Wei Dong Hai-Rui Yang Guo-Li Gu Air Force Clinical College of China Medical University Beijing 100142China Fifth Clinical College(Air Force Clinical College)of Anhui Medical University Beijing 100142China Department of General Surgery Air Force Medical CenterChinese People's Liberation ArmyFifth Clinical(Air Force Clinical College)of China Medical UniversityBeijing 100142China

BACKGROUND Peutz-Jeghers syndrome(PJS) is an autosomal dominant genetic disease with skin mucosal pigment spots and gastrointestinal(GI) multiple hamartoma polyps as clinical characteristics. At present, it is considered that the germline mutation of stk11 gene is the genetic cause of PJS. However, not all PJS patients can be detected stk11 germline mutations. The specific clinical characteristics of these PJS patients without stk11 mutation is an interesting clinical question. Or, like wild type GI stromal tumor, whether these PJS without stk11 mutation are also called PJS is worth discussing. Therefore, we designed the study to understand the clinical characteristics of these PJS patients without stk11 mutation.AIM To investigates whether PJS patients with known stk11 mutations have a more severe spectrum of clinical phenotypes compared to those without.METHODS A total of 92 patients with PJS admitted to the Air Force Medical Center from 2010 to 2022 were randomly selected for study. Genomic DNA samples were extracted from peripheral blood samples, and pathogenic germline mutations of stk11 were detected by high-throughput next-generation gene sequencing. Clinicalpathologic manifestations of patients with and without stk11/LKB1 mutations were compared.RESULTS stk11 germline mutations were observed in 73 patients with PJS. Among 19 patients with no detectable stk11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations. Compared with PJS patients with stk11 mutations, those without tended to be older at the age of initial treatment, age of first intussusception and age of initial surgery. They also had a lower number of total hospitalizations relating to intussusception or intestinal obstruction, and a lower load of small intestine polyps.CONCLUSION PJS patients without stk11 mutations might have less severe clinical-pathologic manifestations than those with.

关键词： Peutz-Jeghers syndrome stk11 Mutant type Wild type

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stk11基因突变与非小细胞肺癌免疫治疗相关性研究进展

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肿瘤防治研究 2022年第8期49卷 850-854页

作者：夏思雨赵梓彤李里哈尔滨医科大学附属第二医院肿瘤内科二病房哈尔滨150086

肺癌是最常见的恶性肿瘤之一。在全球范围内,肺癌的发病率及死亡率都极高且呈上升趋势。近年来,免疫检查点抑制剂(ICIs)在晚期非小细胞型肺癌治疗中产生了显著的生存优势,然而对于驱动基因阳性的非小细胞肺癌患者,免疫检查点抑制剂疗效... 详细信息

肺癌是最常见的恶性肿瘤之一。在全球范围内,肺癌的发病率及死亡率都极高且呈上升趋势。近年来,免疫检查点抑制剂(ICIs)在晚期非小细胞型肺癌治疗中产生了显著的生存优势,然而对于驱动基因阳性的非小细胞肺癌患者,免疫检查点抑制剂疗效不佳。但一些抑癌基因可以通过突变或缺失等方式对免疫治疗产生不同程度的影响,其中丝氨酸/苏氨酸激酶11(stk11)基因突变与PD-1/PD-L1免疫检查点抑制剂有效性密切相关,研究发现stk11突变与免疫细胞浸润减少、PD-L1低表达和对PD-L1抑制反应差有关。本文就非小细胞肺癌中stk11基因突变与免疫治疗相关性的研究进展作一综述。

关键词： stk11 免疫检查点抑制剂非小细胞肺癌基因突变免疫治疗

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Identification of the core promoter of stk11 gene and its transcriptional regulation by p53

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Progress in Natural Science:Materials International 2008年第3期18卷 273-280页

作者： Maojin Yao a,1, Yongjun Wang a,1, Hongwei Shen a, Wenfeng Ning a, Jianguang Tang a, Xiangping Wanga, Jie Li b, Shiquang Zhou a, Xin Yi a, Chenjie Li a, Yi Chu a, Fei Wanga, Xiaoliu Shi a, a The Second Xiang Ya Hospital of Central South University, Changsha 410011, China b Zhu Zhou No.1 Hospital, ZhuZhou 412000, China The Second Xiang Ya Hospital of Central South University Changsha 410011 China Zhu Zhou No.1 Hospital ZhuZhou 412000 China

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. Most cases of PJS involve the inactivation of germline mutations in the serine/threonine kinase gene stk11 which is also known as LKB1. The function of stk11 was previously linked to the tumor suppressor p53 and was shown to activate the p53 target p21/ WAF1. Recently, stk11 was reported to be interacting with p53 physically in the nucleus and it can directly or indirectly phosphorylate p53. Here we characterized the 50-flanking region of human stk11 gene and identified a 161-bp fragment with promoter activity. Sequence analysis, mutagenesis and gel shift studies revealed a binding site of Sp1 and p53, which affects the promoter activity. Mutation analyses showed that this fragment was required for p53-mediated transcriptional activation. This transcriptional activation was further confirmed by real-time quantitative RT-PCR and Western blot analysis. Transient transfection of p53 expression plasmid into fetal liver cell lines increased stk11 mRNA and protein levels. In conclusion, our results reveal a new role for p53 in elevating stk11 gene expres- sion via a positive feedback pattern.

关键词： Peutz-Jeghers syndrome stk11 p53 Promoter transcriptional regulation Tumor suppressor

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Peutz-Jeghers综合征基因型研究及临床诊治进展

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中华结直肠疾病电子杂志 2024年第1期13卷 6-13页

作者：张智董志伟徐祖鑫姜莉鑫张玉辉顾国利中国人民解放军空军特色医学中心普通外科北京100142 安徽医科大学第五临床学院合肥230032 中国医科大学研究生院沈阳110122

Peutz-Jeghers综合征(PJS)是一种临床罕见的常染色体显性遗传病,该病以皮肤黏膜色素斑、胃肠道多发错构瘤息肉和家族遗传性为特征性临床表现,其罹患恶性肿瘤的发生率明显高于正常人群。该病的分子发病机制与抑癌基因stk11功能异常相关,... 详细信息

Peutz-Jeghers综合征(PJS)是一种临床罕见的常染色体显性遗传病,该病以皮肤黏膜色素斑、胃肠道多发错构瘤息肉和家族遗传性为特征性临床表现,其罹患恶性肿瘤的发生率明显高于正常人群。该病的分子发病机制与抑癌基因stk11功能异常相关,但其遗传学背景复杂,临床异质性明显。目前的治疗以消化内镜的镜下治疗为主,辅之以外科手术,可显著延长患者的生存期,但尚无根治性的手段。本文复习了关于该病的相关文献,对其遗传学特性和临床治疗进展进行综述,并对未来的研究方向进行展望。

关键词：遗传性疾病基因型 Peutz-Jeghers综合征临床表型 stk11

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Clinical features, endoscopic polypectomy and stk11 gene mutation in a nine-month-old Peutz-Jeghers syndrome Chinese infant

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World Journal of Gastroenterology 2016年第11期22卷 3261-3267页

作者： Zhi-Heng Huang Zai Song Ping Zhang Jie Wu Ying Huang Department of Gastroenterology Children’s Hospital of Fudan University Department of Pediatric Surgery Children’s Hospital of Fudan University The Molecular Genetic Diagnosis Center Shanghai Key Lab of Birth DefectsTranslational Medicine Research Center of Children’s Development and DiseasePediatrics Research InstituteChildren’s Hospital of Fudan University Department of Gastroenterology Children’s Hospital of Xiamen

AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11(stk11) gene analysis was also performed using a DNA sample from this infant.RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the stk11 gene further revealed a novel frameshift mutation(c.64_65het_del AT) in exon 1 in this PJS infant.CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the stk11 gene mutation is the primary cause of PJS.

关键词： Peutz-Jeghers syndrome Perforation stk11 gene Chinese infant Polyps

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PD-L1高表达伴stk11与KRAS共突变的晚期肺腺癌1例并文献复习

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临床肺科杂志 2022年第5期27卷 789-792页

作者：包淑钧陈杨宋慧慧韦坤辰唐昊海军军医大学第二附属医院呼吸与危重症医学科上海200003

本文报道1例PD-L1高表达(TPS 60%)、stk11与KRAS共突变的晚期肺腺癌患者的诊治经过。该患者经一线至四线方案的积极治疗,疾病始终呈现持续进展(一线使用AC化疗联合帕博利珠单抗治疗,二线白蛋白紫杉醇联合贝伐珠单抗及帕博利珠单抗治疗,... 详细信息

本文报道1例PD-L1高表达(TPS 60%)、stk11与KRAS共突变的晚期肺腺癌患者的诊治经过。该患者经一线至四线方案的积极治疗,疾病始终呈现持续进展(一线使用AC化疗联合帕博利珠单抗治疗,二线白蛋白紫杉醇联合贝伐珠单抗及帕博利珠单抗治疗,三线GP化疗联合帕博利珠单抗治疗,四线采用安罗替尼联合帕博利珠单抗治疗)。

关键词：贝伐珠单抗单抗治疗晚期肺腺癌 stk11 白蛋白紫杉醇突变文献复习

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miR-627-3p并发靶向stk11/KEAP1调控肺腺癌的铁死亡研究

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实用癌症杂志 2023年第7期38卷 1066-1070页

作者：张苗苗田君娜孙颖颖河南省南阳市中心医院 473000

目的探讨miR-627-3p调控肺腺癌铁死亡的潜在机制。方法纳入肺腺癌患者126例,收集肺腺癌组织和癌旁组织后使用miRNA微阵列检测差异miRNA并分析miRNA与肺腺癌患者生存率的相关性。过表达或敲低miRNA后检测肺腺癌细胞Calu-3的增殖水平和铁... 详细信息

目的探讨miR-627-3p调控肺腺癌铁死亡的潜在机制。方法纳入肺腺癌患者126例,收集肺腺癌组织和癌旁组织后使用miRNA微阵列检测差异miRNA并分析miRNA与肺腺癌患者生存率的相关性。过表达或敲低miRNA后检测肺腺癌细胞Calu-3的增殖水平和铁死亡水平。使用miRDB数据库分析miR-627-3p发挥生物学功能的潜在底物,选取评分最高的60个基因进行siRNA敲低筛选以鉴定miR-627-3p的底物。结果miRNA微阵列分析发现有27种miRNA变化显著,其中14种miRNA在肺腺癌组织中表达下调,13种miRNA在肺腺癌组织中表达上调。其中,miR-627-3p高表达的肺腺癌患者生存率优于miR-627-3p低表达的肺腺癌患者。过表达miR-627-3p后,肺腺癌细胞Calu-3的细胞增殖水平下降(Pstk11或KEAP1时肺腺癌细胞Calu-3的细胞增殖水平下降(Pstk11或KEAP1时肺腺癌细胞Calu-3的细胞增殖水平上升(Pstk11或KEAP1的mRNA和蛋白水平下降;敲低miR-627-3p后,肺腺癌细胞Calu-3中stk11或KEAP1的mRNA和蛋白水平上升。此外,miR-627-3p结合stk11或KEAP1的3'端非翻译区。结论miR-627-3p通过并发靶向stk11/KEAP1促进肺腺癌的铁死亡水平。miR-627-3p可能是治疗肺腺癌的有用治疗靶点。

关键词： miR-627-3p stk11 KEAP1 肺腺癌铁死亡

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构建stk11基因融合质粒检测其对肺癌细胞迁移能力的影响

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肿瘤防治研究 2014年第7期41卷 707-710页

作者：张鑫君邱祥南章龙珍王建设丁昕辛勇覃朝晖姚元虎徐州医学院附属医院放射治疗科徐州医学院肿瘤生物治疗实验室江苏徐州221002

目的构建表达stk11(serine/threonine kinase 11,stk11)基因和报告基因EGFP融合蛋白的重组质粒,并转染肺癌A549和H460细胞株,检测其对肺癌细胞迁移能力的影响。方法构建重组质粒pEGFP-stk11,双酶切和测序进行鉴定。重组质粒转染A549和H... 详细信息

目的构建表达stk11(serine/threonine kinase 11,stk11)基因和报告基因EGFP融合蛋白的重组质粒,并转染肺癌A549和H460细胞株,检测其对肺癌细胞迁移能力的影响。方法构建重组质粒pEGFP-stk11,双酶切和测序进行鉴定。重组质粒转染A549和H460细胞株,荧光显微镜观察EGFP蛋白表达情况,Western blot检测stk11蛋白表达情况,划痕实验检测其对肺癌细胞迁移能力的影响。结果酶切和测序结果表明pEGFP-stk11重组质粒构建成功;在转染A549和H460细胞后24h观察到绿色荧光最强;Western blot结果显示stk11蛋白在转染后24 h条带最深;划痕实验显示,转染组细胞迁移距离小于0.9%氯化钠溶液对照组(Pstk11基因重组质粒,并能转染A549和H460细胞,转染后对肺癌细胞迁移能力起一定抑制作用。

关键词： stk11 细胞迁移 A549 H460

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