Background: Chemoresistance has been considered to be a major obstacle for cancer therapy clinically. Long non-coding RNAs (LncRNAs) are asscociated with the development, prognosis and drug-resistance of non-small cell lung cancer (NSCLC). Whereas, the regulatory mechanism of lncRNA TATDN1 in the cisplatin resistance of NSCLC is still not clear. Methods: The expression of TATDN1, miR-451 and TRIM66 in NSCLC tissues and cell lines were detected by qRT-PCR or western blot. Immunohistochemistry (IHC) assay was performed for the detection of TATDN1 expression profile. 88 patients who underwent cisplatin treatment were followed up to 60-months for the analysis of survival rate. MTT and Flow cytometry analysis were performed for the assessment of cell survival rate, proliferation and apoptosis. Bioinformatics, Dual-Luciferase reporter were employed to analyze the interaction among TATDN1, miR-451 and TRIM66. Xenograft tumor model was constructed to verify the role of TATDN1 in NSCLC treated with cisplatin (DDP) in vivo. Results: TATDN1 and TRIM66 was significantly upregulated while miR-451 was downregulated in NSCLC tissues and cell lines, especially in DDP-resistant tumor tissues and cells. Survival rates of NSCLC patients with low TATDN1 expression were improved following DDP chemotherapy. TATDN1 upregulated TRIM66 expression via sponge for miR-451. Moreover, TATDN1 knockdown improved DDP-sensitivity in NSCLC patients by regulation of miR-451/TRIM66 axis. Finally, knockdown of TATDN1 improved the sensitivity of NSCLC to DDP in vivo. Conclusions: TATDN1 enhanced the DDP-tolerance of NSCLC cells by upregulating TRIM66 expression via sponging miR-451, hinting a novel regulatory pathway of chemoresistance in DDP-tolerant NSCLC cells and providing a potential therapeutic target for NSCLC patients with DDP-reistance. ARTICLE HISTORY

Increasing evidence indicates that microRNAs (miRNAs) have essential roles in various biological processes, including proliferation, migration, invasion, cell cycle progression and apoptosis. It is considered that miRNA de-regulation contributes to tumor progression and metastasis in various cancers, and MiR-203a has been identified as a tumor suppressor in cancers, such as glioma, gastric cancer and hepatocellular carcinoma. Herein, we established that miR-203a expression is significantly lower in bladder cancer tissues than in adjacent normal tissues, and that low miR-203a expression is associated with poor patient outcome. The over-expression of miR-203a inhibited bladder cancer cell proliferation, invasion, migration and EMT in vitro, and its up-regulation led to bladder cancer cell cycle arrest and apoptosis. This over-expression also inhibited the PI3K/Akt signaling pathway. Bioinformatics prediction software and luciferase reporter assay then confirmed that SIX4 is a direct target of miR-203a. We established negative correlation between SIX4 expression and miR-203a expression in bladder cancer tissues, and SIX4 silencing caused effects similar to miR-203a up-regulation Furthermore, SIX4 over-expression diminished the effects of miR-203a on bladder cancer cells in vitro. In summary, our study determined that miR-203a down-regulation is closely related to tumorigenesis in bladder cancer; thus suggesting that miR-203a is a potential prognostic marker and a potential target in bladder cancer treatment.

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Mucin1 (MUC1) upregulation in colon cancer has been linked to poor patient outcomes and advanced stage at diagnosis. This is partially due to MUC1-mediated inhibition of T-cell proliferation affecting efficient lysis by cytotoxic lymphocytes, which contributes to escape from immune surveillance. In the present study, human colorectal cancer tissues were collected, and MUC1-positive and MUC1-negative colon cancer mouse models were prepared; subsequently, the number and function of immune cells in tumor tissues were measured using flow cytometry. The present study revealed that MUC1, as a tumor-associated antigen, can recruit more tumor-infiltrating lymphocytes into the tumor microenvironment compared with MUC1-negative colon cancer, but that these cells could not serve antitumor roles. Conversely, the present study demonstrated that MUC1-positive colon cancer attracted more regulatory T cells (Treg cells), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the tumor site than MUC1-negative colon cancer. Furthermore, the data suggested that programmed death protein 1 (PD1)-programmed death ligand 1 (PDL1) expression is greater in MUC1-positive colon cancer. Blocking the PD1-PDL1 signaling pathway reduced the percentage of Treg cells, MDSCs and TAMs in the tumor microenvironment, enhanced T-cell cytotoxicity and inhibited tumor growth, prolonging the survival time of MUC1-positive tumor-bearing mice. Therefore, the present study elucidated the role of MUC1 in tumor immune escape and provides a foundation for the application of PDL1 inhibitors to MUC1-positive colon cancer.

PURPOSE. Retinoblastoma is a malignant tumor of the developing retina that mostly occurs in children. Our study aimed to investigate the effect of tripartite motif-containing protein 59 (TRIM59) on retinoblastoma growth and the underlying mechanisms. METHODS. We performed bioinformatic analysis of three datasets (GSE24673, GSE97508, and GSE110811) from the Gene Expression Omnibus database. Quantitative reversetranscription PCR and immunoblotting of three retinoblastoma cell lines were conducted to verify TRIM59 as a differentially expressed gene. Specific siRNAs were used to inhibit TRIM59 expression in the HXO-Rb44 cell line. A lentiviral vector was transfected into the Y79 cell line to overexpress TRIM59. The effects of TRIM59 on retinoblastoma cell proliferation, cell cycling, and apoptosis were explored in vitro using the abovementioned cell lines. The effect of TRIM59 expression on retinoblastoma cell proliferation was evaluated in a mouse xenograft tumor model. RESULTS. TRIM59 expression in three retinoblastoma cell lines was remarkably elevated compared with normal control. Knocking down TRIM59 expression remarkably suppressed cell proliferation and growth and promoted cell apoptosis in HXO-Rb44 cells, whereas TRIM59 overexpression promoted tumor progression in Y79 cells. Silencing TRIM59 also markedly inhibited in vivo tumor growth in the xenograft model. Mechanistic studies revealed that TRIM59 upregulated phosphorylated p38, p-JNK1/2, p-ERK1/2, and p-c-JUN expression in retinoblastoma cells. Notably, the p38 inhibitor SB203580 attenuated the effects of TRIM59 on cell proliferation, apoptosis, and the G 1 /S phase transition. CONCLUSIONS. TRIM59 plays an oncogenic role in retinoblastoma and exerts its tumorpromotive function by activating the p38-mitogen-activated protein kinase pathway.

SUMMARY OBJECTIVE ADAMTS4 is a member of the ADAMTS4 family, which secretes proteinases. The mechanism of tumor metastasis may be correlated to its promotion of angiogenesis. It was determined whether ADAMTS4 participates in colorectal cancer progression. Methods The expression in clinical samples and CRC cell lines was investigated. Using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and RT-PCR, the expression of ADAMTS4 was determined in colorectal tumors of different cancer stages and anatomic sites, and in three cell lines of different aggressiveness. Results The overexpression of ADAMTS4 was observed in tissue samples by IHC, and this was mainly located in the cytoplasm, as detected by FISH. The qRT-PCR and western blot analyses further supported the clinical sample findings. Conclusion The present data support the notion that the overexpression of ADAMTS4 in CRC might be useful as a non-invasive biomarker for detecting CRC in patients.

Introduction Programmed cell death 1 ligand 1 (PD-L1) can be upregulated in cancer cells via interferon gamma (IFNγ) in the tumor microenvironment. IFNγ/PD-L1 signaling is associated with the response to immune checkpoint blockade in melanoma patients. Our previous investigation indicated that the microsatellite instability-high (MSI-H) cell line might exhibit selective hyperresponsiveness to IFNγ treatment, which contributes to increased PD-L1 expression and may be a mechanism of response to anti-PD-1 therapy in colorectal cancer. Methods The present study evaluated the expression of PD-L1 in a set of MSI and microsatellite stability (MSS) cell lines with IFNγ treatment. The differential signaling molecules associated with signal transducer and activator of transcription (STAT) contributing to hyperresponsiveness to IFNγ exposure were also investigated. Furthermore, we established a coculture assay containing CT26 cells with higher expression of PD-L1 and peripheral blood mononuclear cells (PBMCs) in vitro. Changes in cancer cell viability as well as apoptosis status in response to anti-PD-1 therapy were demonstrated. We further observed changes in the percentage of CD4 + and CD8 + lymphocytes after PD-1 immunotherapy in the coculture assay. Finally, the average extent of inflammation and adaptive immunity factors in the assay was also investigated. Results This in vitro study revealed that the MSI cell line might exhibit hyperresponsiveness to IFNγ exposure, and IFNγ induced upregulation of PD-L1 mainly through increased STAT1 and decreased STAT3 signaling. IFNγ/PD-L1 signaling participated in the response to anti-PD-1 therapy mainly through the CTL profile. Discussion Our findings reinforce previous knowledge of the fact that the response to immune checkpoint blockade occurs mainly in patients with a preexisting intratumoral IFNγ/PD-L1 signal, thus suggesting potential therapeutic strategies to enhance responsiveness to PD-1 blockade immunotherapy in most patients with colorectal cancer.