Background/Aims: Krüppel-like factor 4 (KLF4), a member of the KLF family of zinc finger transcription factors, has been identified as a tumor suppressor gene in a variety of tumors. However, the molecular mechanisms by which KLF4 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in pancreatic cancer remain unclear. Methods: KLF4 expression in pancreatic cancer was analyzed using public datasets (Oncomine and The Cancer Genome Atlas). The expression of KLF4, caveolin-1 (Cav-1), E-cadherin, and vimentin, and their correlations with clinicopathological characteristics were evaluated by immunohistochemistry in pancreatic cancer tissues. The biological functions and underlying mechanisms of KLF4 expression on EMT and metastasis were also investigated in vitro and in vivo. Results: Public datasets showed that KLF4 expression was significantly decreased in pancreatic cancer and correlated with the depth of invasion and disease stage. The expression of KLF4, Cav-1, E-cadherin, and vimentin protein in pancreatic cancer tissues was closely associated with pathological grade, disease stage, and metastasis. KLF4 expression was also positively correlated with E-cadherin expression and negatively correlated with vimentin expression, whereas Cav-1 expression was negatively associated with E-cadherin expression and positively correlated with vimentin expression. Knockdown of KLF4 expression promoted EMT and facilitated pancreatic cancer cell growth and metastasis in vitro and in vivo. In addition, immunohistochemistry (IHC) results indicated that KLF4 expression was negatively correlated with Cav-1 expression. Furthermore, down-regulating KLF4 expression increased Cav-1 and vimentin expression and decreased E-cadherin expression. Mechanistically, KLF4 could transcriptionally inhibit Cav-1 expression by binding directly to the promoter domain of Cav-1. Conclusions: KLF4 inhibits pancreatic cancer EMT and metastasis by down-regulating Cav-1 expression, suggesting that the KLF4/Cav-1 signaling pathway may be a novel diagnostic and therapeutic target.
Breast cancer is a kind of malignant tumor that severely threatens women's lives and health worldwide. Tumor‐associated macrophages (TAMs) have been reported to mediate tumor progression, while the mechanism still needs further identification. In this study, we found that M2 macrophages promoted increased cell proliferation and migration as well as reduced expression of interferon regulatory factor 7 (IRF7) and increased the expression of miR‐1587 in breast cancer cells. Overexpression of IRF7 or miR‐1587 knockdown reversed M2 macrophage‐induced cell proliferation and migration as well as tumor growth in vivo. Mechanistically, miR‐1587 targeted the 3ʹ‐untranslated region (3ʹ‐UTR) of IRF7 mRNA to regulate its protein expression leading to tumor progression. Collectively, this study revealed that the miR‐1587/IRF7 axis mediates M2 macrophage‐induced breast cancer progression, and this sheds light on further clinical therapy for breast cancer by targeting TAMs as well as the miR‐1587/IRF7 axis.
MiR-301a is as an oncogene involved in the regulation of gastric cancer (GC) progression, but the underlying mechanism is unclear. This study was to explore the lncRNA PCAT18/miR-301a/TP53INP1 axis in regulating the GC cell proliferation and metastasis. In the present study, GC tissues and cell lines were collected for the detection of PCAT18 expression. Herein, we found that, PCAT18 is significantly decreases in human GC tissues and five GC cell lines. Overexpression of PCAT18 inhibits cell viability, invasion, and migration of GC cells and tumor growth of GC xenograft tumors. PCAT18 negatively regulates the expression level of miR-301a. The interaction between PCAT18 and miR-301a is confirmed by RIP and RNA pull down. MiR-301a mimic increases cell viability and promotes cell migration and invasion and reverses the inhibitory action of PCAT18. TP53INP1 expression is negatively regulated by miR-301a and TP53INP1/miR-301a is involved in GC viability, migration, and invasion. The promoting of PCAT18 on TP53INP1 expression is abolished by miR-301a overexpression. In conclusion, lncRNA PCAT18 acts as a tumor suppressor for GC and lncRNA PCAT18, miR-301a, and TP53INP1 comprise a signal axis in regulating GC cell proliferation, migration, and invasion.
Dysregulation of circRNAs is reported to exert crucial roles in cancers, including hepatocellular carcinoma (HCC). So far, the function of circRNAs in HCC development remains poorly known. Currently, our data showed that circ_0008305 was highly elevated in HCC cell lines and 30 paired tissue samples of HCC. As evidenced, suppression of circ_0008305 repressed HCC cell growth significantly. Meanwhile, up‐regulation of circ_0008305 significantly reduced HCC cell growth. Mechanistically, we displayed that circ_0008305 could bind with miR‐186 by using bioinformatics analysis. miR‐186 has been reported to be a crucial tumour oncogene in many cancers. In addition, we proved miR‐186 was greatly decreased in HCC. The direct correlation between miR‐186 and circ_0008305 was confirmed in our work. In addition, up‐regulation of miR‐186 obviously restrained HCC progression. Increased expression of transmembrane p24 trafficking protein 2 (TMED2) is significantly related to the unfavourable outcomes in cancer patients. At our present work, we proved that TMED2 could act as a direct target of miR‐186. Mechanistically, we demonstrated that circ_0008305 up‐regulated TMED2 expression by sponging miR‐186, which resulted in significantly induced HCC progression in vitro and in vivo. These revealed the significant role of circ_0008305 in HCC progression, which might indicate a new perspective on circRNAs in HCC development.
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