lncRNA HIT000218960 enhances resistance to 5-fluorouracil by promoting HMGA2 and activating the AKT/mTOR/P70S6K pathway in gastric cancer cells.

The aim of the present study was to investigate the effect of the long noncoding RNA HIT000218960 on gastric cancer cell resistance to 5-fluorouracil (5-FU) and to explore the underlying molecular mechanism. HIT000218960 expression was measured in gastric cancer tissues and cells lines using reverse transcription-quantitative PCR and western blotting. Gastric cancer cell lines with overexpressed or repressed HIT000218960 levels were generated to study its influence on apoptosis induced by 5-FU, which was analyzed using flow cytometry analysis. Compared with those in normal gastric mucosal tissues and non-cancerous gastric mucosal epithelial cells, HIT000218960 and high mobility group A2 (HMGA2) proteins were found to be upregulated in gastric cancer tissues and cells. Additionally, a positive correlation was found between the expression of HIT000218960 and HMGA2 in gastric cancer tissues. In patients with gastric cancer, HIT000218960 expression was revealed to associate negatively with the efficacy of chemotherapy and 3-year overall survival rate. Overexpression of HIT000218960 suppressed apoptosis in SNU-5 cells, whilst HIT000218960 knockdown increased the apoptosis of NCI-N87 cells following 5-FU treatment. Downstream, HIT000218960 was demonstrated to promote HMGA2 protein expression in gastric cancer cells. In these cells, knocking down HMGA2 expression significantly increased apoptosis in addition to reducing AKT, mTOR and P70S6 kinase (P70S6K) phosphorylation after 5-FU treatment. In conclusion, HIT000218960 is overexpressed in gastric cancer tissues and cells, which is associated with the efficacy of chemotherapy. Mechanistically, this may be mediated by the upregulation HMGA2 expression and AKT/mTOR/P70S6K signaling.

Combination Therapy of Metastatic Castration-Recurrent Prostate Cancer: Hyaluronic Acid Decorated, Cabazitaxel-Prodrug and Orlistat Co-Loaded Nano-System.

PURPOSE: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. METHODS: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. RESULTS: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. CONCLUSION: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

Long non-coding RNA HIT000218960 is associated with poor prognosis in patients with gastric cancer.

Long non-coding RNAs (lncRNAs) have been indicated to have important roles in the development of malignant tumors. In the present study, the expression of HIT000218960 in gastric cancer (GC) tissues was assessed and its clinical significance was analyzed. It was revealed that HIT000218960 was highly expressed in GC tissues and HIT000218960 levels in GC tissues from 103 cases were positively correlated with high mobility group AT-hook 2 (HMGA2) mRNA expression. Furthermore, HIT000218960 was significantly associated with tumor diameter, TNM stage, histological grade, the number of lymph nodes with metastasis and HMGA2 expression in tumor tissues of patients with GC. The results of the univariate and multivariate Cox regression analysis indicated that HIT000218960 expression was a factor affecting the prognosis of patients with GC. In addition, patients with GC with lower HIT000218960 or HMGA2 expression had more favorable 3-year survival, while HIT000218960 expression did not affect the 3-year overall survival of patients with GC with different levels of HMGA2 expression. In conclusion, HIT000218960 was highly expressed in patients with GC and was related to poor prognosis.

IRF-1 mediated long non-coding RNA PVT1-214 promotes oxaliplatin resistance of colorectal cancer via miR-128 inhibition.

PURPOSE: Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1-214 transcript (PVT1-214) is a notable lncRNA involved in gastric cancer and colorectal cancer (CRC) so far. Nowadays, the biological function of PVT1-214 on the response of CRC to chemotherapy is still unclear. We aimed to explore the molecular mechanism of PVT1-214 and its regulatory mechanism in advanced CRC. METHODS: The levels of PVT1-214, microRNA (miR)-128, and interferon regulatory factor-1 (IRF-1) in CRC tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Log-rank test was applied to evaluate the role of high PVT1-214 levels in shortening the overall survival of CRC patients. Chi-square test was to assess the relation between PVT1-214 expression and clinicopathological features of CRC patients. CCK8 assays tested the cell proliferation of oxaliplatin-resistant CRC cells (HCT116/Oxa and SW480/Oxa) with PVT1-214 knockdown. The underlying regulatory mechanism between PVT1-214 and miR-128 was predicted by bioinformatics and verified by RNA transfection, qRT-PCR and western blotting. Chromatin immunoprecipitation (ChIP) assay was done to examine the relationship between or IRF-1 and the PVT1-214 gene. RESULTS: High levels of PVT1-214 expression were more likely to be present in patients with late-stage (IV), chemotherapy resistance, and inferior overall survival. PVT1-214 was aberrantly elevated in oxaliplatin-resistant CRC tissues and cell lines (HCT116/Oxa and SW480/Oxa). PVT1-214 knockdown reduced cell proliferation, migration and invasion of oxaliplatin-resistant CRC cells in vitro. Moreover, IRF-1 was found to be a negative transcription regulator of PVT1-214 and decreased PVT1-214 levels in oxaliplatin-resistant CRC cells. Besides, PVT1-214 repressed miR-128 function by binding to the complementary sites of miR-128. CONCLUSIONS: IRF-1/PVT1-214 may markedly boost the oxaliplatin-resistance of CRC, resulting in the late TNM stage and poor survival. These findings suggest that the IRF-1/PVT1-214 axis may be a helpful target for intervention in CRC.

CXCL13/CXCR5 are potential biomarkers for diagnosis and prognosis for breast cancer.

PURPOSE: Breast cancer is known as the second frequent cancer in the world, even as the most common cancer among women. This study aimed to explore the correlation of CXCL13/CXCR5 expression with clinical characteristics in breast cancer and evaluate their potential to be used as biomarkers in diagnosis and prognosis of this disease. METHODS: A total of 133 female patients diagnosed with breast cancer were collected. The expression of CXCL13 and CXCR5 mRNA was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining. RESULTS: The expression of CXCL13 and CXCR5 was significantly higher in breast cancer tissue than in normal breast tissues, with a high correlation coefficient of 0.9973. Positive cell numbers and positive expression rates of CXCL13 and CXCR5 in cancer breast tissue were much higher than those in normal breast tissue, and raised with increase of cancer stage. The high expression of CXCL13 and CXCR5 in breast cancer tissue was notably associated with lymph node metastasis, distant metastasis, disease stage, but not with age, Her-2 status, histological type or tumor size. Immunohistochemistry analysis showed that the positive expression of CXCL13 and CXCR5 was related with cancer stage, Also, positive expression of CXCL13 was correlated with positive expression of CXCR5. Patient age, Her-2 status, tumor size, histological type, and lymph node metastasis were independent factors for the 5-year survival rate of breast cancer patients, whereas the 5-year survival was correlated with distant metastasis and expression of CXCL13 and CXCR5. CONCLUSIONS: These results suggested that CXCL13 and CXCR5 expressions could act as potential biomarkers for breast cancer diagnosis and prognosis.