Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

Recent studies have implied that miRNAs may play a crucial role in tumor progression and may be involved in the modulation of some drug resistance in cancer cells. Earlier studies have demonstrated that miR-194 was involved in tumor metastasis and drug resistance in non-small cell lung cancer (NSCLC), whereas their expression and roles on NSCLC still need further elucidation. In the current study, we found that miR-194 is decreased in NSCLC samples compared with adjacent non-cancerous lung samples, and low expression of miR-194 predicts poor patient survival. Both in vitro and in vivo experiments showed that ectopic stable expression miR-194 suppressed proliferation, migration, invasion and metastasis and induced apoptosis in NSCLC cells and that this suppression could be reversed by reintroducing forkhead box A1 (FOXA1), a functional target of miR-194. In addition, miR-194 was downregulated in in cisplatin-resisted human NSCLC cell line-A549/DDP and overexpression of miR-194 increases cisplatin sensitivity. These findings suggested that miR-194 inhibits proliferation and metastasis and reverses cisplatin-resistance of NSCLC cells and may be useful as a new potential therapeutic target for NSCLC.

Anaplastic thyroid cancer (ATC) is associated with poor prognosis and is often untreatable. MicroRNA 483-3p (miR-483) and partitioning-defective 3 (Pard3), a member of the Pard family, have functions and regulatory mechanisms in ATC. The abnormal regulation of miR-483 may play an important role in tumorigenesis, and Par3 is known to regulate cell polarity, cell migration, and cell division. Tumor proliferation promoted by the regulation of miRNA expression can be regulated in thyroid cancer by upregulating transforming growth factor-β1 (TGF-β1), which is thought to interact with Pard3. When compared with adjacent non-tumor tissues, we found that miR-483 was upregulated and Pard3 was downregulated in 80 thyroid tumor samples. Disease-free survival was decreased when expression of miR-483 was upregulated and Pard3 expression was downregulated. Cell growth, migration, and invasion were induced by overexpression of miR-483. However, knockdown of miR-483 resulted in a loss of cell invasion and viability, both in vitro and in vivo. The expression of Pard3 was increased by the inhibition of miR-483, but TGF-β1-induced cell migration and invasion were decreased by miR-483 inhibition. A dual-luciferase reporter assay determined that Pard3 expression was downregulated when targeted with miR-483. The epithelial-mesenchymal transition (EMT), as well as Tiam1-Rac signaling, was induced by TGF-β1, which was decreased by the overexpression of Pard3. Pard3 decreased the inhibition of EMT and Tiam-Rac1 signaling, which resulted from transfection of ATC cells with miR-483. Overall, the results showed that downregulation of Pard3 resulted in increased cell invasion and EMT in ATC, which was promoted by treatment with miR-483. These findings suggest novel therapeutic targets and treatment strategies for this disease.