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1.
Gastric Cancer ; 25(1): 96-106, 2022 01.
Article in English | MEDLINE | ID: mdl-34370147

ABSTRACT

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.


Subject(s)
Stomach Neoplasms , Animals , Cell Line, Tumor , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Mice , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Sirolimus/pharmacology , Sirolimus/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology
3.
Asian Pac J Cancer Prev ; 15(1): 161-6, 2014.
Article in English | MEDLINE | ID: mdl-24528019

ABSTRACT

Lung cancer is the most common causes of cancer-related deaths worldwide, and a lack of effective methods for early diagnosis has greatly impacted the prognosis and survival rates of the affected patients. Tumor-initiating cells (TICs) are considered to be largely responsible for tumor genesis, resistance to tumor therapy, metastasis, and recurrence. In addition to representing a good potential treatment target, TICs can provide clues for the early diagnosis of cancer. MicroRNA (miRNA) alterations are known to be involved in the initiation and progression of human cancer, and the detection of related miRNAs in TICs is an important strategy for lung cancer early diagnosis. As Hsa-miR-155 (miR-155) can be used as a diagnostic marker for non-small cell lung cancer (NSCLC), a smart molecular beacon of miR-155 was designed to image the expression of miR-155 in NSCLC cases. TICs expressing CD133 and CD338 were obtained from A549 cells by applying an immune magnetic bead isolation system, and miR-155 was detected using laser-scanning confocal microscopy. We found that intracellular miR- 155 could be successfully detected using smart miR-155 molecular beacons. Expression was higher in TICs than in A549 cells, indicating that miR-155 may play an important role in regulating bio-behavior of TICs. As a non-invasive approach, molecular beacons could be implemented with molecular imaging to diagnose lung cancer at early stages.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/chemistry , Lung Neoplasms/chemistry , MicroRNAs/analysis , Neoplastic Stem Cells/chemistry , AC133 Antigen , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/analysis , Antigens, CD/analysis , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Gene Expression , Glycoproteins/analysis , Humans , Immunomagnetic Separation , Lung Neoplasms/genetics , MicroRNAs/genetics , Microscopy, Confocal , Neoplasm Proteins/analysis , Peptides/analysis
4.
Asian Pac J Cancer Prev ; 13(3): 761-6, 2012.
Article in English | MEDLINE | ID: mdl-22631644

ABSTRACT

OBJECTIVE: Although various human cancer stem cells (CSCs) have been defined, their applications are restricted to immunocompromised models. Developing a novel CSC model which could be used in immunocompetent or transgenic mice is essential for further understanding of the biomolecular characteristics of tumor stem cells. Therefore, in this study, we analyzed murine lung cancer cells for the presence of CSCs. METHODS: Side population (SP) cells were isolated by fluorescence activated cell sorting, followed by serum-free medium (SFM) culture, using Lewis lung carcinoma cell (LLC) line. The self-renewal, differentiated progeny, chemosensitivity, and tumorigenic properties in SP and non-SP cells were investigated through in vitro culture and in vivo serial transplantation. Differential expression profiles of stem cell markers were examined by RT-PCR. RESULTS: The SP cell fraction comprised 1.1% of the total LLC population. SP cells were available to grow in SFM, and had significantly enhanced capacity for cell proliferation and colony formation. They were also more resistant to cisplatin in comparison to non-SP cells, and displayed increased tumorigenic ability. Moreover, SP cells showed higher mRNA expression of Oct-4, ABCG2, and CD44. CONCLUSION: We identified SP cells from a murine lung carcinoma, which possess well-known characteristics of CSCs. Our study established a useful model that should allow investigation of the biological features and pharmacosensitivity of lung CSCs, both in vitro and in syngeneic immunocompetent or transgenic/knockout mice.


Subject(s)
Carcinoma, Lewis Lung/pathology , Neoplastic Stem Cells , Side-Population Cells , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/genetics , Animals , Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Separation , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Flow Cytometry , Hyaluronan Receptors/biosynthesis , Hyaluronan Receptors/genetics , Mice , Mice, Inbred C57BL , Neoplastic Stem Cells/metabolism , Octamer Transcription Factor-3/biosynthesis , Octamer Transcription Factor-3/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Side-Population Cells/metabolism
5.
Mol Cells ; 33(3): 277-83, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22349807

ABSTRACT

Increasing evidence demonstrates that miRNAs are involved in the dysregulation of tumor initiating cells (TICs) in various tumors. Due to a lack of definitive markers, cell sorting is not an ideal separation method for lung adenocarcinoma initiating cells. In this study, we combined paclitaxel with serum-free medium cultivation (inverse-induction) to enrich TICs from A549 cells, marked by CD133/CD326, defined features of stemness. We next investigated aberrant microRNAs in this subpopulation compared to normal cells with miRNA microarray and found that 50 miRNAs exhibited a greater than 2-fold change in expression. As further validation, 10 miRNAs were chosen to perform quantitative RT-PCR on the A549 cell line and primary samples. The results suggest that aberrant expression of miRNAs such as miR-29ab, miR-183, miR-17-5p and miR-127-3P may play an important role in regulating the bio-behavior of TICs.


Subject(s)
Adenocarcinoma/metabolism , Antigens, CD/metabolism , Antigens, Neoplasm/metabolism , Cell Adhesion Molecules/metabolism , Glycoproteins/metabolism , Lung Neoplasms/metabolism , MicroRNAs/metabolism , Neoplastic Stem Cells/metabolism , Peptides/metabolism , AC133 Antigen , Adenocarcinoma/pathology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Epithelial Cell Adhesion Molecule , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genes, Neoplasm , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , MicroRNAs/genetics , Neoplasm Transplantation , Neoplastic Stem Cells/drug effects , Oligonucleotide Array Sequence Analysis , Paclitaxel/pharmacology , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism
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