Background: Helicobacter pylori (H. pylori) is a carcinogenic factor for gastric cancer. Our previous study demonstrated that H. pylori decreased the expression of microRNA(miRNA)-30a to promote the tumorigenesis in gastric cancer. However, the upstream regulatory mechanism of miR-30a hasn't wellelucidated. In this study, we found the long non-coding RNA (lncRNA) NEAT1 may sponge miR-30a to regulate COX-2/BCL9 pathway.Methods: The expression of NEAT1 was detected in gastric cancer tissues and tumour adjacent tissues by uorescence in-situ hybridization(FISH) analysis and RT-qPCR. LncRNA-miRNA interaction networks were constructed using the RNAhybird and Starbase v.2.0. and then validated using dual-luciferase assay.The effects of NEAT1 dysregulation on the proliferative, migratory and invasive abilities of H. pylori ltrate infected gastric cancer cells were observed by cell counting kit-8 (CCK-8), colony formation, wound healing test and transwell assays. Western blot and RT-qPCR were performed to detect protein and RNA expression. The Immunohistochemistry(IHC) was carried out to analyze the location and expression of COX-2 and BCL9Results: FISH and RT-qPCR demonstrated that the expression of NEAT1 was up-regulated in gastric cancer tissues, especially in H. pylori gastric cancer tissues, and the expression of NEAT1 is negatively correlated with miR-30a(miR-30a-3p, miR-30a-5p).The proliferation, migration and invasion of H. pylori ltrate infected gastric cancer cells could be largely enhanced by the up-regulation of NEAT1, while the downregulation of NEAT1 decreased these abilities, and miR-30a could reverse the effect of NEAT1 on these abilities. Dual-luciferase assay identi ed that NEAT1 directly targeted miR-30a (miR-30a-3p, miR-30a-5p).Due to miR-30a(miR-30a-3p, miR-30a-5p) negatively regulated the expression of downstream COX-2 and BCL9, NEAT1 was identi ed to indirectly upregulate the expression of COX-2 and BCL9.IHC showed that the expression of COX-2 and BCL9 were increased in H. pylori gastric cancer tissues. Conclusion:The study demonstrated that lncRNA NEAT1 may act as a promoter of tumorigenesis in H. pylori gastric cancer, by sponging miR-30a(miR-30a-3p, miR-30a-5p) to regulate COX-2/BCL9 pathway.

The circadian rhythm is generated at the cellular level by a molecular clock system that involves specific genes. Studies have revealed that circadian clock disruption is a control point in cancer progression. Colorectal cancer (CRC) is one of the cancers closely associated with circadian disruption. In the present review, the involvement of the circadian clock in CRC development was summarized. Abnormal expression of certain clock genes has been found in patients with CRC and their correlation with clinicopathological features has also been explored. The period and cryptochrome 2 (Cry2), Sirtuin1 (SIRT1) and neuronal PAS domain protein 2 (NPAS2) genes were reported to have tumour suppressor properties. Conversely, Cry1, brain and muscle ARNT-like-1, circadian locomotor output cycles kaput (CLOCK) and timeless may aggravate CRC progression, but these findings are not consistent and require to be confirmed by further research. Circadian scheduling also indicated advantages in chemotherapy treatments for patients with CRC by increasing the maximum tolerated doses and decreasing toxicities. Dysfunction of the molecular CLOCK system disrupted cellular processes to accelerate colon tumorigenesis, such as metabolism, cell cycle, DNA damage repair, proliferation and apoptosis, epithelial-mesenchymal transition and stemness. The clock gene network and how the dynamics of the system influence CRC were discussed.

Background Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered. Methods A reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer. Results Luciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo. Conclusions In summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis. Graphical Abstract