MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation.

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis.

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

LINC01559 accelerates pancreatic cancer cell proliferation and migration through YAP-mediated pathway.

Pancreatic cancer (PC) is one of the top two most fatal cancers, with the poorest survival rate among all human malignancies. Increasing evidence suggests the involvement of long noncoding RNAs (lncRNAs) in the initiation and progression of various cancers. Herein, we investigated the role of lncRNA LINC01559 in PC. Several online databases indicated that LINC01559 was at a low expression in normal pancreatic tissues but was obviously upregulated in PAAD tissues. Further, our results showed that LINC01559 was stimulated in PC cell lines relative to normal controls. Furthermore, we validated that LINC01559 facilitated PC cell proliferation and migration in vitro. Also, silencing LINC01559 obstructed PC cell growth in vivo. Besides, LINC01559 was revealed to be mainly in the cytoplasm of PC cells and therefore served as a ceRNA of Yes-associated protein (YAP) in PC cells via sponging miR-607. Surprisingly, we also proved that LINC01559 could interact with YAP protein, which might hinder YAP phosphorylation and enhance YAP transcriptional activity in PC cells. Furthermore, we demonstrated that YAP was the downstream effector in LINC01559-regulated PC development. Collectively, our findings unmasked that LINC01559 accelerates PC progression through relying on YAP, providing a new potential target for clinical treatment of patients with PC.

Panax ginseng polysaccharide suppresses metastasis via modulating Twist expression in gastric cancer.

It was previously reported that an antitumor polysaccharide (PGPW1) was isolated from the root of Panax ginseng. To extend our study, we investigated here the anti-invasive and metastatic effects of PGPW1 on human gastric cancer cell line HGC-27 and tried to determine its possible mechanism of action. Both scratch wound-healing and Transwell assay identified that PGPW1 dose-dependently inhibited migration and invasiveness of HGC-27 cells. Furthermore, results of western blot showed that protein levels of Twist and AKR1C2 were inhibited by PGPW1, whereas an increase of NF1 was observed. Moreover, down-regulation of Twist expression by PGPW1 blocked epithelial-mesenchymal transition (EMT), characterized by a gain of epithelial cell markers, E-cadherin, and loss of the mesenchymal markers, vimentin and N-cadherin, at protein levels. Collectively, we confirmed that PGPW1 decreased migration and invasion of HGC-27 cells by regulation of Twist, AKR1C2, NF1, E-cadherin, vimentin and N-cadherin expression. In conclusion, PGPW1 may serve as a powerful chemopreventive agent against gastric cancer metastasis.