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BackgroundThrombospondin-2 (TSP-2) is a secreted matricellular glycoprotein that is found to mediate cell-to-extracellular matrix attachment and participates in many physiological and pathological processes. The expression profile of TSP-2 on tumors is controversial, and it up-regulates in some cancers, whereas it down-regulates in others, suggesting that the functional role of TSP-2 on tumors is still uncertain.MethodsThe expression of TSP-2 on prostate cancer progression was determined in the tissue array by the immunohistochemistry. The molecular mechanism of TSP-2 on prostate cancer (PCa) metastasis was investigated through pharmaceutical inhibitors, siRNAs, and miRNAs analyses. The role of TSP-2 on PCa metastasis in vivo was verified through xenograft in vivo imaging system.ResultsBased on the gene expression omnibus database and immunohistochemistry, we found that TSP-2 increased with the progression of PCa, especially in metastatic PCa and is correlated with the matrix metalloproteinase-2 (MMP-2) expression. Additionally, through binding to CD36 and integrin ανβ3, TSP-2 increased cell migration and MMP-2 expression. With inhibition of p38, ERK, and JNK, the TSP-2-induced cell migration and MMP-2 expression were abolished, indicating that the TSP-2’s effect on PCa is MAPK dependent. Moreover, the microRNA-376c (miR-376c) was significantly decreased by the TSP-2 treatment. Furthermore, the TSP-2-induced MMP-2 expression and the subsequent cell motility were suppressed upon miR-376c mimic stimulation. On the other hand, the animal studies revealed that the bone metastasis was abolished when TSP-2 was stably knocked down in PCa cells.ConclusionsTaken together, our results indicate that TSP-2 enhances the migration of PCa cells by increasing MMP-2 expression through down-regulation of miR-376c expression. Therefore, TSP-2 may represent a promising new target for treating PCa.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0390-6) contains supplementary material, which is available to authorized users.

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Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a β-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, β-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study. K E Y W O R D S lung cancer, melatonin, stemness, Twist 1 | INTRODUCTION Lung cancer is a major occasion of cancer mortality. Non-small cell lung cancer (NSCLC) is the most general type of lung cancer, accounting for more than 85% of all lung cancers. 1,2 Although chemotherapy and radiotherapy have improved lung cancer treatment over the past few decades, survival rates remain poor, with approximately 15% of patients remaining alive at 5 years after diagnosis. This poor prognosis is due to metastasis in the late stage of disease. Cells with a stem-like, dormant phenotype, endowed with unlimited self-renewal and high tumorigenic capability, are deemed responsible for post-therapy relapse and metastatic dissemination in various cancers, including lung cancer. 3-5 Therefore, the drugs that attack the cancer stem cells (CSCs) population have therapeutic benefit.Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal grand and other organs, is produced in a circadian rhythm in reply to photic signaling from the retina. 6,7 Melatonin is important for controlling the immune system 8-10 and has an antioxidant effect. 11,12 This agent protects cells against carcinogenic substances and inhibits the development, metastasis, invasion and angiogenesis of many types

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The epithelial–mesenchymal transition (EMT) phenotype, whereby mature epithelial cells undergo phenotype transition and differentiate into motile, invasive cells, has been indicated in tumor metastasis. The melatonin hormone secreted by the pineal gland has an antioxidant effect and protects cells against carcinogenic substances that reduce tumor progression. However, the effects of melatonin in EMT and lung cancer metastasis are largely unknown. We found that melatonin down-regulated EMT by inhibiting Twist/Twist1 (twist family bHLH transcription factor 1) expression. This effect was mediated by MT1 receptor, PLC, p38/ERK and β-catenin signaling cascades. Twist expression was positively correlated with tumor stage and negatively correlated with MT1 expression in lung cancer specimens. Furthermore, melatonin inhibited EMT marker expression and lung cancer metastasis to liver in vivo. Finally, melatonin shows promise in the treatment of lung cancer metastasis and deserves further study.

Background/Aims: Whether single large hepatocellular carcinoma (SLHCC) is classified as Barcelona Clinic Liver Cancer (BCLC) stage A or B is still controversial. We aimed to compare the clinical manifestations, treatment modalities, and prognoses among patients with SLHCC and those in BCLC stage A and B. Methods: We enrolled 2,285 treatment-naive hepatocellular carcinoma (HCC) patients with BCLC stage A or B from October 2007 to December 2015. Factors in terms of prognoses were analyzed by multivariate analysis. Results: We enrolled 1,210, 466, and 609 patients in a BCLC-A, SLHCC, and BCLC-B group, respectively. After a median follow-up duration of 21.2 months, 898 patients had died. The cumulative 5-year survival rates were 57.0, 42.6, and 27.3% for patients in the BCLC-A, SLHCC, and BCLC-B groups, respectively, which were significantly different (p < 0.001). Multivariate analysis indicated that the following independent risk factors were associated with poor prognosis: age > 65 years, alkaline phosphatase > 100 U/L, creatinine > 1.0 mg/dL, alpha-fetoprotein > 20 mg/mL, noncurative treatment, albumin-bilirubin (ALBI) grade, and HCC staging. Subgroup analysis also confirmed that patients in the SLHCC group had a survival rate intermediate to those in the BCLC-A and BCLC-B groups. However, for patients in the SLHCC group and with ALBI grade 1, outcomes were close to those in the BCLC-A group, especially in the setting of curative treatment. For those with ALBI grades 2 or 3, the prognoses were similar to those of the SLHCC and BCLC-B groups. Conclusion: Patients in the SLHCC group had an overall survival rate intermediate to those of the BCLC-A and BCLC-B groups. It is suggested that the SLHCC group could be classified as occupying a different stage from the BCLC stages A and B. The ALBI grade could help to stratify SLHCC into a different prognostic group. However, the results need to be validated externally in other regions of the world.

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