piplartine and Carcinoma--Hepatocellular

Researches have pointed that piplartine inhibits the proliferation of hepatocellular carcinoma (HCC) cells, however, the underlying mechanisms has not been well defined. Currently, more and more studies have pointed out that circRNAs can regulate tumor cell proliferation, involve in the tumorigenesis mechanism of various tumors. In this study, we explored whether piplartine may participate in the development of HCC through the regulation of ability of HCC cell proliferation by circRNA. Based on the chip analysis, we selected candidate circRNAs that are highly correlated with HCC. CircRNA expression in OSCC cells treated with piplartine was detected by qRT-PCR. We found that only the expression of hsa_circ_100338 (circ-100338) was observably reduced. The expression characteristics of circ-100338 in HCC cell lines were also verified by qRT-PCR. Subsequently, whether or notcirc-100338 can regulate ZEB1 via competitively binding to miR-141-3p was determined by the RIP assay and dual luciferase reporter gene assay. The effect of the circ-100338/miR-141-3p/ZEB1 axis on the proliferation of HCC cell was tested by EdU and CCK-8 assay. Results showed that circ-100338 expression was observably increased in HCC cell lines. Simultaneously, circ-100338 can regulate the expression of ZEB1by competitively binding to miR-141-3p. Moreover high expression of circ-100338 can stimulate the proliferation of HCC cells. Our current study revealed that circ-100338 played as a ceRNA in promoting the progression of HCC by sponging miR-141-3p, while piplartine can participate in the development of HCC by inhibiting the expression of circ-100338.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidones; RNA, Circular; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Although piplartine is regarded as an anticancer agent, the relationship between long noncoding RNAs (lncRNAs), which are involved in various diseases (e.g., tumors) and piplartine in hepatocellular carcinoma (HCC) remains unclear. We identified LINC01391 using microarray analysis and validated its expression by qRT-PCR. Functional assays were applied to evaluate the biological effects of LINC01391 and inhibitory of β-catenin and T-cell factor (ICAT) on HepG2 and SMMC-7721 cells. The binding relationship between LINC01391 and ICAT was determined by RNA pull-down and RNA immunoprecipitation (RIP). Results showed that piplartine attenuated cell proliferation and invasion but promoted cell apoptosis. Upregulation of LINC01391 induced by piplartine inhibited HCC cell proliferation, invasion in vitro, and tumor growth in vivo. LINC01391 interacted with ICAT and promoted its inhibitory effect on the Wnt/β-catenin pathway, as enhanced interaction between β-catenin and ICAT, and dampened interaction of β-catenin and TCF/LEF were induced by overexpression of LINC01391. Knockdown of ICAT also promoted cell proliferation in vitro and tumor growth in vivo. Our study supported a role for piplartine and LINC01391 in HCC treatment. We found that LINC01391 inhibited the Wnt/β-catenin pathway and suppressed tumor growth via ICAT.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Mice, Nude; Neoplasm Invasiveness; Piperidones; RNA, Long Noncoding; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Hepatocellular carcinomas (HCC) are highly malignant and aggressive tumors lack of effective therapeutic drugs. Piperlongumine (PL), a natural product isolated from longer pepper plants, is recently identified as a potent cytotoxic compound highly selective to cancer cells. Here, we reported that PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway. PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 µM while PL at much lower concentrations only suppressed HCC cell migration/invasion. PL selectively elevated reactive oxygen species (ROS) in HCC cells, which activated or up-regulated downstream PERK/Ire 1α/Grp78, p38/JNK/Erk and CHOP subsequently. Administration of antioxidants completely abolished PL's effects on cell death and migration/invasion. However, pharmacological inhibition of ER stress-responses or MAPKs signaling pathways with corresponding specific inhibitors only reversed PL's effect on cell migration/invasion but not on cell death. Consistently, knocking-down of CHOP by RNA interference only reversed PL-suppressed HCC cell migration. Finally, PL significantly suppressed HCC development and activated the ER-MAPKs-CHOP signaling pathway in HCC xenografts in vivo. Taken together, PL selectively killed HCC cells and preferentially inhibited HCC cell migration/invasion via ROS-ER-MAPKs-CHOP axis, suggesting a novel therapeutic strategy for the highly malignant and aggressive HCC clinically.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Dioxolanes; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Liver Neoplasms; Male; MAP Kinase Signaling System; Mice; Rats; Rats, Wistar; Reactive Oxygen Species; Transcription Factor CHOP; Transfection