ABSTRACT
BACKGROUND: Intellectual disability (ID) is characterized by an IQ < 70, which implies below-average intellectual function and a lack of skills necessary for daily living. ID may occur due to multiple causes, such as metabolic, infectious, and chromosomal causes. ID affects approximately 1-3% of the population; however, the cause can be identified in only 25% of clinical patients. METHODS: To find the cause of genetic ID in a family, we performed whole-exome sequencing and Sanger sequencing to confirm the presence of a SETBP1 variant and real-time quantitative polymerase chain reaction to detect SETBP1 expression in the proband and normal controls. RESULTS: A novel variant, c.942_943insGT (p. Asp316TrpfsTer28), was found in SETBP1. Furthermore, we observed that SETBP1 expression in patients was only 20% that of normal controls (P < 0.05). CONCLUSION: A heterozygous variant in SETBP1 associated with ID was found. This report provides further evidence for its genetic basis and support for clinical genetic diagnosis.
Subject(s)
Intellectual Disability , Humans , Intellectual Disability/genetics , East Asian People , Family , Asian People/genetics , Pedigree , Mutation , Carrier Proteins/genetics , Nuclear Proteins/geneticsABSTRACT
BACKGROUND: The incidence of colorectal cancer (CRC) is considered to be the third-highest malignant tumor among all carcinomas. The alterations in cellular bioenergetics (metabolic reprogramming) are associated with several malignant phenotypes in CRC, such as tumor cell proliferation, invasion, metastasis, chemotherapy resistance, as well as promotes its immune escape. However, the expression pattern of metabolism-associated genes that mediate metabolic reprogramming in CRC remains unknown. METHODS: In this study, we screened out CPT2 by investigating the function of a series of metabolism-related genes in CRC progression by integrating the data from the TCGA and GEO databases. Next, we collected CRC tissues (n = 24) and adjacent non-tumor tissues (n = 8) and analyzed mRNA levels by qRT-PCR, and proteins levels of CPT2 in CRC cell lines by western blotting. CCK-8 assay, colony formation assay, Edu assay and flow cytometry assay were performed to assess the effects of CPT2 on proliferation in vitro. RESULTS: We identified 236 metabolism-related genes that are differentially expressed in colorectal cancer, of which 49 up-regulated and 187 down-regulated, and found CPT2 as the most significant gene associated with favorable prognosis in CRC. It was revealed that CPT2 expression was consistently down-regulated in CRC cell lines and tissues. Moreover, knockdown of CPT2 could promote the proliferative ability of CRC cells, whereas over-expression of CPT2 significantly suppressed the cell growth. CONCLUSION: In summary, CPT2 can provide new insights about the progression and occurrence of the tumor as it acts as an independent prognostic factor in CRC sufferers.
Subject(s)
Colorectal Neoplasms , Biomarkers , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Prognosis , RNA, MessengerABSTRACT
Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.
Subject(s)
Colorectal Neoplasms , Animals , Carcinogenesis/genetics , Cell Proliferation/genetics , Cell Transformation, Neoplastic , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Down-Regulation , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Humans , Mice , Oxaliplatin/pharmacologyABSTRACT
Integrin ß4 (ITGß4) is a class of transmembrane adhesion molecules composed of hemidesmosomes (HDs). Its unique long intracellular domain provides intricate signal transduction functions. These signal transduction effects are especially prominent in tumors. Many recent studies have shown that integrin ß4 is differentially expressed in various tumors, and it plays a vital role in tumor invasion, proliferation, epithelial-mesenchymal transition, and angiogenesis. Therefore, we categorize the research related to integrin ß4, starting from its structure and function in tumor tissues, and provide a basic description. Based on its structure and function, we believe that integrin ß4 can be used as a tumor marker. In clinical practice, it is described as a diagnostic marker for the targeted treatment of cancer and will be helpful in the clinical diagnosis and treatment of tumors.
