RESUMO
BACKGROUND: Altered miR-188-3p expression has been observed in various human cancers. AIM: To investigate the miR-188-3p expression, its roles, and underlying molecular events in gastric cancer. METHODS: Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression. Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays. The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay. A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival. A nude mouse tumor cell xenograft assay was used to confirm the in vitro data. RESULTS: MiR-188-3p was found to be lower in the plasma of gastric cancer patients, tissues, and cell lines compared to their healthy counterparts. It was associated with overall survival of gastric cancer patients (P < 0.001), tumor differentiation (P < 0.001), lymph node metastasis (P = 0.033), tumor node metastasis stage (I/II vs III/IV, P = 0.024), and American Joint Committee on Cancer stage (I/II vs III/IV, P = 0.03). Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy. CBL was identified as a direct target of miR-188-3p, with its expression antagonizing the effects of miR-188-3p on gastric cancer (GC) cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway. The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer. CONCLUSION: The current data provides ex vivo, in vitro, and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.
RESUMO
Radiotherapy has long been considered as the mainstay of treatment for nasopharyngeal carcinoma (NPC). However, locoregional recurrence or distant metastasis may occur in some patients due to the radiation resistance of cancer cells. Autophagy plays a vital role in protecting cells against radiation. However, the mechanism of autophagy in radiation therapy remains obscure. In the present study, we demonstrated that suppression of autophagy related 5 (Atg5) aggravated ionizing radiation (IR)-induced DNA damage and apoptosis in human NPC cells without accelerating the cell cycle, whereas regulation of the cell cycle has been widely regarded as the most important determinant of IR sensitivity. Further study showed that inhibition of autophagy suppressed the mRNA expression of Rad51, a key protein of homologous recombination that has been demonstrated to play a critical role in the repair of DNA double-strand breaks induced by radiation. Moreover, suppression of Atg5 had no impact on the radiosensitivity when cells were pre-treated by the Rad51 inhibitor, and the enhanced radiosensitivity by Atg5 suppression was reversed by overexpression of Rad51 in human NPC cells. Our results suggest that inhibition of autophagy enhances the susceptibility of NPC cells to radiation by reducing Rad51 expression. Therefore, Rad51 targeted therapy may be investigated as a potential novel agent for the adjuvant treatment of traditional radiation of NPC.