Extracellular vesicular lncRNA FAL1 promotes hepatocellular carcinoma cell proliferation and invasion by inducing macrophage M2 polarization

Current evidence finds that circulating exosomal lncRNA focally amplified lncRNA on chromosome 1 (FAL1) promotes the progression of hepatocellular carcinoma (HCC). However, the underlying mechanism of serum extracellular vesicular FAL1 in HCC progression remains elusive. Here, we extracted extracellular vesicles (EVs) from serum samples of HCC patients and healthy volunteers, and found that FAL1 was highly enriched in the serum EVs of HCC patients. Then, macrophages were treated with EVs alone or together with small interfering RNA against FAL1 (si-FAL1). The data indicated that FAL1-enriched EVs induced macrophage M2 polarization, while silencing FAL1 in macrophages antagonized the role of EVs. Moreover, HepG2 cells were co-cultured with the conditioned macrophages, and co-culturing with EVs-incubated macrophages promoted HepG2 cell proliferation, invasion, cell cycle progression, and colony formation, and inhibited cell apoptosis and sorafenib sensitivity, while interfering FAL1 in macrophages reversed these effects. Consistently, ectopic expression of FAL1 in macrophages also induced macrophage M2 polarization, and co-culture of FAL1-overexpressing macrophages with HepG2 cells facilitated the malignant progression of HepG2 cells. Furthermore, co-culturing HepG2 cells with EVs-incubated macrophages activated the Wnt/β-catenin signaling pathway, and treatment with a Wnt/β-catenin pathway inhibitor IWP-2 partially neutralized the effect of EVs-incubated macrophages on HepG2 cell malignant behaviors. Additionally, FAL1 enriched EVs-incubated macrophages markedly increased mouse xenograft tumor growth. In conclusion, extracellular vesicular lncRNA FAL1 promotes macrophage M2 polarization and further activates the Wnt/β-catenin signaling pathway in HCC cells, thus promoting HCC progression. (AU)

Extracellular vesicular lncRNA FAL1 promotes hepatocellular carcinoma cell proliferation and invasion by inducing macrophage M2 polarization.

Current evidence finds that circulating exosomal lncRNA focally amplified lncRNA on chromosome 1 (FAL1) promotes the progression of hepatocellular carcinoma (HCC). However, the underlying mechanism of serum extracellular vesicular FAL1 in HCC progression remains elusive. Here, we extracted extracellular vesicles (EVs) from serum samples of HCC patients and healthy volunteers, and found that FAL1 was highly enriched in the serum EVs of HCC patients. Then, macrophages were treated with EVs alone or together with small interfering RNA against FAL1 (si-FAL1). The data indicated that FAL1-enriched EVs induced macrophage M2 polarization, while silencing FAL1 in macrophages antagonized the role of EVs. Moreover, HepG2 cells were co-cultured with the conditioned macrophages, and co-culturing with EVs-incubated macrophages promoted HepG2 cell proliferation, invasion, cell cycle progression, and colony formation, and inhibited cell apoptosis and sorafenib sensitivity, while interfering FAL1 in macrophages reversed these effects. Consistently, ectopic expression of FAL1 in macrophages also induced macrophage M2 polarization, and co-culture of FAL1-overexpressing macrophages with HepG2 cells facilitated the malignant progression of HepG2 cells. Furthermore, co-culturing HepG2 cells with EVs-incubated macrophages activated the Wnt/ß-catenin signaling pathway, and treatment with a Wnt/ß-catenin pathway inhibitor IWP-2 partially neutralized the effect of EVs-incubated macrophages on HepG2 cell malignant behaviors. Additionally, FAL1 enriched EVs-incubated macrophages markedly increased mouse xenograft tumor growth. In conclusion, extracellular vesicular lncRNA FAL1 promotes macrophage M2 polarization and further activates the Wnt/ß-catenin signaling pathway in HCC cells, thus promoting HCC progression.

Effect of lncRNA FAL1 on Chemotherapy Resistance of Ovarian Cancer Cells by Regulating MAPK Pathway and Related Mechanism / 肿瘤防治研究

Objective To observe the expression difference of lncRNA FAL1 in ovarian cancer cells and their drug-resistant cell lines, and to explore the effect and mechanism of lncRNA FAL1 down-regulation on cell chemotherapy resistance. Methods The expression levels of fal1 gene in SKOV3 and COC1 cells and their drug-resistant cell lines were detected by qRT-PCR. fal1 siRNA was transfected to downregulate fal1 gene expression. MTT was used to detect cell proliferation. Transwell method was used to detect cell invasion ability. Plate clone formation test was used to detect cell clone ability, and Western blot was used to detect MDR-1, mpr-1, ABCG2 and phosphorylation levels of p38 MAPK, ERK1/2 and JNK. SKOV3/DDP and COC1/DDP cells transfected with FAL1-siRNA were injected subcutaneously into BALB/c nude mice. The volume and mass of subcutaneous transplanted tumors were measured. Results Compared with SKOV3 and COC1 cells, SKOV3/DDP and COC1/DDP cells were less sensitive to DDP, and the expression levels of FAL1 gene increased (P < 0.01). After transfection with FAL1-siRNA, the sensitivity of SKOV3/DDP and COC1/DDP cells to DDP increased (P < 0.01), and the invasion (P < 0.05) and cloning ability (P < 0.01) decreased. The expression levels of MDR-1, MPR-1, ABCG2 (P < 0.01) and the phosphorylation levels of p38 MAPK, ERK1/2 and JNK (P < 0.05) decreased. The volume and mass of subcutaneous transplanted tumors were significantly reduced (P < 0.01). Conclusion Down-regulation of lncRNA FAL1 could significantly reduce the chemotherapy resistance of cisplatin-resistant ovarian cancer cell lines and inhibit the proliferation of drug-resistant cells in vivo. Its mechanism is related to inhibiting the activation of MAPK signaling pathway.

LncRNA FAL1 promotes carcinogenesis by regulation of miR-637/NUPR1 pathway in colorectal cancer.

LncRNA FAL1 has been demonstrated to play an important role in promoting carcinogenesis via the ceRNA mechanism in several types of cancer. However, the role and the mechanism of lncRNA FAL1 in CRC remain unclear. Here our results demonstrate that lncRNA FAL1 is markedly upregulated in CRC tissues and cells, and lncRNA FAL1 promotes proliferation ability, migration and invasion in CRC cells. Additionally, we demonstrate that lncRNA FAL1 acts as a sponge of miR-637, which functions as a suppressor via targeting and downregulation of NUPR1 expression. Moreover, we demonstrate that lncRNA FAL1 promotes carcinogenesis of CRC cells via regulation of the miR-637/NUPR1 pathway. Taken together, our findings underscore the crucial roles of lncRNA FAL1 in CRC carcinogenesis and its potential prognostic and therapeutic value.

LncRNA FAL1 promotes cell proliferation and migration by acting as a CeRNA of miR-1236 in hepatocellular carcinoma cells.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been demonstrated to play crucial role in tumor growth and metastasis for hepatocellular carcinoma (HCC). LncRNA FAL1 has been indicated to promote the progression of various cancers. However, the role of lncRNA FAL1 in HCC was poorly understood. METHODS: The expression levels of lncRNA FAL1 in HCC tissues and cells were determined by RT-qPCR. The roles of lncRNA FAL1 on HCC cells were investigated by MTT, colony formation, transwell, RT-qPCR, and Western blotting. The miRNA binding sites of lncRNA FAL1 was predicted using RegRNA 2.0 and miR-1236 was validated to target lncRNA FAL1 by luciferase reporter assays and RT-qPCR. Finally, the expression levels of lncRNA FAL1 in serum exosome of HCC patients was also investigated and the role of exosome-mediated lncRNA FAL1 was further investigated by co-culturing with HCC cells. RESULTS: This study first showed that lncRNA FAL1 was up-regulated in HCC tissues and functioned as an oncogene in HCC. LncRNA FAL1 could accelerate cell proliferation and metastasis as a ceRNA mechanism by competitively binding to miR-1236. Moreover, lncRNA FAL1 was also up-regulated in serum exosome of HCC patients and could transfer lncRNA FAL1 to HCC cells to increase their abilities of cell proliferation and migration. CONCLUSIONS: Taken together, this study indicated that lncRNA FAL1 functions as an oncogenic in HCC and may be a novel diagnostic biomarker or a novel target for the treatment of HCC in future.