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1.
World J Clin Cases ; 10(20): 7105-7115, 2022 Jul 16.
Article in English | MEDLINE | ID: mdl-36051147

ABSTRACT

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant hereditary disorder because of germline mutations in DNA mismatch repair genes, such as MutL homolog 1 (MLH1), PMS1 homolog 2, MutS homolog 2, and MutS homolog 6. Gene mutations could make individuals and their families more susceptible to experiencing various malignant tumors. In Chinese, MLH1 germline mutation c.(453+1_454-1)_(545+1_546-1)del-related LS has been infrequently reported. Therefore, we report a rare LS patient with colorectal and endometrioid adenocarcinoma and describe her pedigree characteristics. CASE SUMMARY: A 57-year-old female patient complained of irregular postmenopausal vaginal bleeding for 6 mo. She was diagnosed with LS, colonic malignancy, endometrioid adenocarcinoma, secondary fallopian tube malignancy, and intermyometrial leiomyomas. Then, she was treated by abdominal hysterectomy, bilateral oviduct oophorectomy, and sentinel lymph node resection. Genetic testing was performed using next-generation sequencing technology to detect the causative genetic mutations. Moreover, all her family members were offered a free genetic test, but no one accepted it. CONCLUSION: No tumor relapse or metastasis was found in the patient during the 30-mo follow-up period. The genetic panel sequencing showed a novel pathogenic germline mutation in MLH1, c.(453+1_454-1)_(545+1_546-1)del, for LS. Moreover, cancer genetic counseling and testing are still in the initial development state in China, and maybe face numerous challenges in the further.

2.
Sci Rep ; 10(1): 14768, 2020 09 08.
Article in English | MEDLINE | ID: mdl-32901049

ABSTRACT

Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.


Subject(s)
Biomarkers, Tumor/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Ovarian Neoplasms/pathology , RNA, Long Noncoding/genetics , STAT3 Transcription Factor/metabolism , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Biomarkers, Tumor/genetics , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Humans , Mice , Mice, Nude , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Prognosis , STAT3 Transcription Factor/genetics , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
3.
Cancer Drug Resist ; 2(2): 210-224, 2019.
Article in English | MEDLINE | ID: mdl-35582716

ABSTRACT

The centrosome is an organelle that serves as the microtubule- and actin-organizing center of human cells. Although the centrosome is small of size, it is great important on cellular function that regulates cytoskeletal organization and governs precise spindle orientation/positioning ensuring equal distribution of cellular components in cell division. Epigenetic modifications to centrosome proteins can lead to centrosome aberrations, such as disorganized spindles and centrosome amplification causing aneuploidy and genomic instability. Epigenetic disturbances are associated not only with carcinogenesis and cancer progression, but also with drug resistance to chemotherapy. In this review, we discuss mechanisms of epigenetic alteration during the centrosome biogenesis in cancer. We provide an update on the current status of clinical trials that aim to target epigenetic modifications in centrosome aberrations and to thwart drug resistance.

4.
Int J Oncol ; 53(5): 2180-2190, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30226587

ABSTRACT

Ovarian cancer has a high mortality rate among women worldwide. Radiotherapy is considered an effective method of ovarian cancer treatment, however, radioresistance presents a challenge. It is necessary to develop techniques that can increase radiosensitivity in ovarian cancer, and gene therapy is a promising option. The aim of the present study was to investigate the effects of metadherin (MTDH) silencing on the radiosensitivity of ovarian cancer. Ovarian cancer tissues (n=273) and normal ovarian tissues (n=277) were used, as were SKOV3 ovarian cancer cells and the immortalized human ovarian epidermal HOSEpiC cell line. MTT, Transwell and wound-healing assays were performed to assess the proliferation, invasion and migration abilities of the SKOV3 cells. Colony-forming assays and flow cytometry were applied to detect the radiosensitivity and apoptosis of the SKOV3 cells. Nude mouse xenograft models were established to evaluate the effect of MTDH gene silencing on tumor growth and the efficacy of radiotherapy. Ovarian cancer, in tissues and cells, was demonstrated to have a high level of MTDH. Additionally, MTDH silencing was found to significantly inhibit proliferation, migration and invasion, and induce apoptosis in SKOV3 cells, and it was suggested that MTDH depletion significantly increased the sensitivity of the SKOV3 cells to X-ray radiation. MTDH silencing enhanced radiosensitivity and delayed tumor growth in the nude mouse xenograft model. Collectively, the results obtained in the present study suggest the potential role of MTDH silencing as a technique for ameliorating radioresistance in ovarian cancer. The present study provides a promising experimental basis for the improvement of ovarian cancer radiotherapy treatment.


Subject(s)
Cell Adhesion Molecules/genetics , Genetic Therapy/methods , Ovarian Neoplasms/radiotherapy , RNA Interference , Radiation Tolerance/genetics , Adult , Animals , Apoptosis/genetics , Apoptosis/radiation effects , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , Cell Movement/genetics , Cell Movement/radiation effects , Cell Proliferation/genetics , Cell Proliferation/radiation effects , Female , Humans , Membrane Proteins , Mice , Mice, Nude , Middle Aged , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ovary/pathology , Ovary/radiation effects , RNA, Small Interfering/metabolism , RNA-Binding Proteins , Xenograft Model Antitumor Assays , Young Adult
5.
PLoS One ; 12(8): e0183622, 2017.
Article in English | MEDLINE | ID: mdl-28859117

ABSTRACT

Ovarian cancer's poor progression is closely associated with overexpression of matrix metalloproteinase 9 (MMP-9), which belongs to the class of enzymes believed to be involved in the degradation of extracellular matrix. However, the mechanisms underlying regulation of MMP-9 are not completely understood. STAT (signal transducer and activator of transcription) family of transcription factors is well known to be engaged in diverse cellular functions. Activation of STAT3 has been observed in a number of cancers, promoting tumorigenesis and metastasis via transcriptional activation of its target genes. In this study, we tested our hypothesis that STAT3 regulates MMP-9 gene expression in epithelial ovarian cancer. Using epithelial ovarian cancer cell lines as in vitro model, we show an abundance of phosphorylated STAT3 at Tyr705 (p-STAT3) in SKOV3 cell line. We further show that MMP-9 gene promoter was significantly enriched by p-STAT3, and IL-6 treatment led to a significant increase of MMP-9 at mRNA and protein levels, in addition to an association of p-STAT3 with MMP-9 gene. By using luciferase reporter assay, we determined that the STAT3 DNA responsive element of MMP-9 was sufficient to regulate transcriptional activity of a heterologous promoter. These results suggest that the phosphorylation of STAT3 regulates MMP-9 production in ovarian cancer, which might be responsible for its invasiveness and metastasis.


Subject(s)
Cell Proliferation/genetics , Matrix Metalloproteinase 9/biosynthesis , Neoplasms, Glandular and Epithelial/genetics , Ovarian Neoplasms/genetics , STAT3 Transcription Factor/genetics , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Interleukin-6/metabolism , Matrix Metalloproteinase 9/genetics , Neoplasm Invasiveness/genetics , Neoplasm Metastasis , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/pathology , Phosphorylation , Signal Transduction
6.
Oncol Rep ; 34(5): 2296-304, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26324021

ABSTRACT

The presence of cancer stem cells in cervical cancer stem cells (CSCs) is important in the prevention of therapy failure and tumor recurrence. Upregulation of transcriptional regulation of redox sensing factor Nrf2 leads to the overexpression of drug efflux proteins such as ABCG2 in cancer stem cells and thus results in cancer treatment failure and cancer relapse. In the present study, we purified approximately 3.1% of cervical CSCs, which exhibited aberrant upregulation of Nrf2 in conjunction with an elevated transcriptional regulation of ABCG2, Bcl-2 and Bmi-1. Consequently, CSCs possess prolonged cell survival, infinite cell proliferation and highly resistant apoptosis. Following silencing of the function of Nrf2 the cervical CSCs became more sensitive to DNA targeting drugs and apoptosis. Our results suggested that Nrf2-mediated drug and apoptosis resistance are important in cancer therapies and tumor recurrence. Therefore, designing anticancer drugs targeting Nrf2 may be crucial to prevent CSC-mediated tumorigenesis.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Gene Expression Regulation, Neoplastic , NF-E2-Related Factor 2/metabolism , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/physiology , Polycomb Repressive Complex 1/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Adult , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Survival , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Gene Expression , Humans , Mice, Inbred NOD , Mice, SCID , NF-E2-Related Factor 2/genetics , Neoplasm Proteins/genetics , Neoplasm Transplantation , Oxidation-Reduction , Polycomb Repressive Complex 1/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology
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