Abnormal expression of long non-coding RNA (lncRNAs) often contributes to unrestricted growth and invasion of cancer cells. LncRNA XIST expression is up-regulated in several cancers, however, its modulatory mechanism in gastric cancer (GC) has not been elucidated. In the present study, we found that XIST expression was significantly increased in GC tissues and cell lines. LncRNA XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to GC cell growth. LncRNA XIST also contributed to GC cell invasion both in vitro and in vivo. We revealed that XIST functioned as competing endogenous RNA to repress miR-497, which controlled its down-stream target MACC1. We proposed that XIST was responsible for GC cell proliferation and invasion and XIST exerted its function through the miR-497/MACC1 axis. Our findings suggested that lncRNA XIST may be a candidate prognostic biomarker and a target for new therapies in GC patients.

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment (TME) which are closely associated with the tumor malignant progression. However, the regulatory mechanisms by which TAMs influence the progression of triple-negative breast cancer (TNBC) remain unclear. Here, we report that hepatic leukemia factor (HLF) acts as a novel oncoprotein in TNBC. We found that HLF was regulated by transforming growth factor-beta1 (TGF-β1) that is secreted by TAMs. Then, HLF transactivated gamma-glutamyltransferase 1 (GGT1) to promote the ferroptosis resistance, thus driving TNBC cell proliferation, metastasis and cisplatin resistance. Reciprocally, IL-6 produced by TNBC cells activated the JAK2/STAT3 axis to induce TGF-β1 secretion by TAMs, thus constituted a feed-forward circuit. The accuracy of TNBC patient prognosis could be improved by employing a combination of HLF and GGT1 values. Thus, our findings document that the interactive dialogue between TNBC cells and TAMs promotes sustained activation of HLF in tumor cells through the IL-6-TGF-β1 axis. Subsequently, HLF promotes the ferroptosis resistance in TNBC cells via GGT1 and ultimately facilitates the malignant tumor progression. Our study provides a potential target for the treatment of TNBC.

Abstract. As a member of the tissue inhibitor of metalloproteinases (TIMP) family, it has been reported that TIMP-3 is involved in human cancer development. However, the function of TIMP-3 in hepatocellular carcinoma (HCC) development is unclear. We aimed to determine the biological role of TIMP-3 in HCC by evaluating the effects of its methylation status and expression on HCC cell function. TIMP-3 expression in HCC tissues was visibly analyzed by immunohistochemistry. Methylation of the TIMP-3 promoter was evaluated by methylation-specific PCR. Effects of TIMP-3 on HCC cell growth, apoptosis, migration, and invasion were examined by transfecting the TIMP-3-expressing plasmid, pCMV6. TIMP-3 was expressed in non-tumorous live tissue, but silenced or downregulated in 60% of HCC cases (P<0.05). Reduced protein expression of TIMP-3 was associated with reduced tumor differentiation (P=0.003) and increased metastatic activity (P=0.005) in HCC cell lines. Promoter methylation contributed to the TIMP-3 inactivation. Overexpression of TIMP-3 in HCC cell lines suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. TIMP-3 expression is suppressed by promoter methylation in HCC. This inhibitory protein acts as a functional tumor suppressor by inhibiting HCC cell proliferation, invasion, and migration and by inducing apoptosis and cell cycle arrest at the G2/M phase.

The variation in the (AAT)n repeat of the CNR1 gene conferred an increased risk for developing IBS, while rs324420 (C385) in the FAAH gene was not associated with IBS pathogenesis.