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MicroRNAs (miRs) are involved in the development and progression of hepatocellular carcinoma (HCC), but the regulatory mechanism of miR-98 in HCC still remains unclear. Here we found that miR-98 was significantly downregulated in HCC tissues compared to matched adjacent normal tissues (ANTs). Low miR-98 expression was associated with tumor size, metastasis, portal vein tumor embolus, and poor overall survival. Ectopic expression of miR-98 decreased the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells. SALL4 was identified as a novel target of miR-98, and the protein expression of SALL4 was inhibited by miR-98 in HCC cells. Overexpression of SALL4 reversed the suppressive effects of miR-98 on the malignant phenotypes of HCC cells. Besides, SALL4, upregulated in HCC tissues compared to the matched ANTs, was inversely correlated to the miR-98 levels in HCC tissues. In addition, overexpression of miR-98 markedly suppressed the tumor growth as well as tumor-induced death in nude mice. In summary, miR-98 plays a suppressive role in the proliferation, migration, invasion and EMT of HCC cells, partly at least, via directly inhibition of SALL4. Therefore, the miR-98/SALL4 axis may become a promising therapeutic target for HCC.

Nonalcoholic fatty liver disease (NAFLD) is typified by accumulating excess liver triacylglycerol, inflammation, and liver dysfunction. This study was aimed to investigate the role of mitochondrial DNA synthesis-induced activation of Absent in melanoma 2 (AIM2) inflammasome and pyroptosis in NAFLD. Mice were raised on a high-fat diet for 24 weeks to establish NAFLD models. F4/80 immunofluorescence was performed to reflect the inflammatory response in the liver of mice. Western blot, ELISA, and immunofluorescence were adopted to determine the expression of AIM2 inflammasome-related proteins and factors. EdU immunofluorescence was applied for the examination of mitochondrial DNA expression and flow cytometry for cell pyroptosis. Agarose gel electrophoresis was used to detect the integrity of extracted mouse mitochondrial DNA (mtDNA). The levels of AIM2 inflammasome-related proteins in the liver and the levels of IL-1β and IL-18 in serum were elevated in high-fat diet-induced NAFLD mice. AIM2 inflammasome activation and pyroptosis were triggered, and suppressed activation of AIM2 inflammasome alleviated the inflammation and pyroptosis in the liver of NAFLD mice. Mitochondria were severely damaged and mtDNA was synthesized after NAFLD modeling. Further, mtDNA treatment could promote palmitate (PA)-induced activation of AIM2 inflammasome and pyroptosis. Moreover, inhibition of IRF1 gene alleviated PA-induced AIM2 inflammasome activation and pyroptosis. In conclusion, mitochondrial DNA synthesis could enable AIM2 inflammasome activation and induce the hepatocyte pyroptosis, thereby exacerbating NAFLD.

Pancreatic cancer is one of the most lethal types of cancer, and curative resection is only applicable to potentially limited cases due to early metastasis and local invasion. This study reports the influence of CXCL12 and its receptor CXCR4 on the progression of pancreatic cancer and highlights the correlation between the CXCL12/CXCR4 axis and the organ-specific metastasis of pancreatic adenocarcinoma (PAC). A total of 34 patients with pancreatic cancer participated in the current study. The expression of CXCL12 and CXCR4 in cancerous tissues, paracancerous tissues, normal pancreas and lymph nodes surrounding the pancreas were investigated using immunohistochemistry and RT-PCR; furthermore, their relationship with clinicopathological factors was explored (PV9000 method). The positive rate of CXCL12 protein was 13.3% (4/30), the positive rate of CXCR4 protein was 80% (24/30) in tumor tissues. Additionally, a significant correlation between the expression pattern of the CXCL12/CXCR4 axis with lymph node metastasis was identified (P<0.05), excluding gender, age, tumor node metastasis (TNM) stage and differentiation (all P>0.05). Also, the positive rate of CXCL12 protein was 50% (15/30), the positive rate of CXCR4 protein was 73.3% (22/30) in the lymphocytes in lymph nodes surrounding the pancreas. Furthermore, we found that CXCL12 and CXCR4 expression in paratumorous vessels and neural tissue were significantly strongly positive. The paratumorous vessels and neural tissue with positive CXCL12 and CXCR4 expression were invaded by CXCL12-positive pancreatic cancer cells. The chemotactic interaction between CXCR4 and its ligand CXCL12 may be a critical event during the progression of pancreatic cancer. The CXCL12/CXCR4 axis plays an important role in the progression and organ-specific metastasis of pancreatic adenocarcinoma.

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