Recently, pancreatic ductal adenocarcinoma (PDAC) has emerged as one of the most aggressive malignant tumors with the worst prognosis. Previous studies have demonstrated that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is increased in pancreatic cancer and is identified as a diagnostic biomarker. Nonetheless, the molecular mechanism of elevated MALAT1 levels and tumor aggressiveness remains unknown. In this study, MALAT1 was found to be highly expressed in PDAC tissues, and elevated expression was associated with poorer prognoses. In addition, MALAT1 was positively linearly correlated with the expression of LC3B mRNA. Furthermore, several molecules involved in cellular autophagic flux were modulated following the downregulation of MALAT1, including LC3, P62, and LAMP-2. Mechanistically, we found that MALAT1 interacted with RNA binding protein HuR, and silencing of MALAT1 greatly enhanced the posttranscriptional regulation of TIA-1 and had further effects on inhibiting autophagy. MALAT1 was speculated to regulate tumorigenesis via HuR-TIA-1-mediated autophagic activation. Hence, we investigated the biological properties of MALAT1 in terms of tumor proliferation and metastasis by promoting autophagy in vitro In brief, these data demonstrate that MALAT1 could facilitate the advanced progression of tumors in vivo Our study highlights the new roles of MALAT1 on protumorigenic functioning and anticancer therapy via activating autophagy in pancreatic cancer. Mol Cancer Ther; 15(9); 2232-43. ©2016 AACR.

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

Inhibition of NF-κB activation is one of the mechanisms that DHA inhibits angiogenesis in human pancreatic cancer. We also suggest that DHA could be developed as a novel agent against pancreatic cancer.