Exosomal lncRNA PCAT1 Promotes Tumor Circulating Cell-Mediated Colorectal Cancer Liver Metastasis by Regulating the Activity of the miR-329-3p/Netrin-1-CD146 Complex

Abstract

Objective. This study explored the colorectal cancer exosome lncRNA prostate cancer associated transcript 1– (PCAT1) mediated circulating tumors and the mechanism of cell colorectal cancer liver metastasis. Methods. Exosomes were extracted from the primary colorectal cancer (CRC) cell lines HCT116 and SW480 and cultured with T84 and human umbilical vein endothelial (HUVE) cells. The expression of PCAT1 and miR-329-3p was detected by real-time quantitative polymerase chain reaction (RT-qPCR), the expression of Netrin-1, CD146, and epithelial mesenchymal transition (EMT) related proteins was detected by Western blot, the proliferation activity of T84 cells was detected by cell counting kit 8 (CCK-8), and cell migration was detected by Transwell. The expression of the F-actin signal was detected by immunofluorescence after coculture of exosomes with human umbilical vein endothelial cells (HUVECs). Changes in subcutaneous tumor and liver nodule size after PCAT1 deletion were observed in a mouse model of liver metastasis from rectal cancer. Results. PCAT1 expression was upregulated in primary cell lines and their exosomes. After exosomes were cocultured with colorectal cancer tumor circulating T84 cells, the expression of Netrin-1 and CD146 was upregulated, the expression of miR-329-3p was downregulated, the proliferation and migration ability of T84 cells were enhanced, and EMT occurred. After knocking down PCAT1, the above phenomenon was reversed. Similarly, after exosomes were cocultured with HUVECs, the expression of the F-actin signal increased, and after PCAT1 was knocked down, the F-actin signal also decreased. PCAT1 regulates miR-329-3p/Netrin-1 and affects the biological behavior of T84 and F-actin signal expression in HUVECs. In a mouse model of colorectal cancer liver metastasis, knocking down PCAT1 significantly reduced the nodules formed by liver metastasis in mice. Conclusions. LncRNA PCAT1 derived from colorectal cancer exosomes regulates the activity of the Netrin-1-CD146 complex in circulating tumor cells (CTCs) to promote the occurrence of colorectal cancer EMT and liver metastasis and provides new molecular targets for the treatment of colorectal cancer liver metastasis.

Nanotherapeutic approaches for delivery of long non-coding RNAs: an updated review with emphasis on cancer

“…EMT requires the downregulation of E-cadherin in CTCs and the upregulation of N-cadherin and vimentin induced by PCAT1. 175 The correlation between lncRNAs and CRC highlights their involvement in the development of tumors, specifically via exosomal mechanisms. By promoting the development of cancerassociated fibroblasts and pro-tumorigenic tumor-associated macrophages, exosomal lncRNAs influence the tumor microenvironment and advance CRC.…”

“…EMT requires the downregulation of E-cadherin in CTCs and the upregulation of N-cadherin and vimentin induced by PCAT1. 175…”

Connection of Cancer Exosomal LncRNAs, Sponging miRNAs, and Exosomal Processing and Their Potential Modulation by Natural Products

“…Many exosomal lncRNAs have been reported to be overexpressed in cancer cells [ 32 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. However, their potential sponging miRNAs are rarely reported.…”

“…Several reported exosomal lncRNAs are summarized ( Table 1 ). HEIH [ 40 ], LINC02418 [ 41 ], POU3F3 [ 40 ], GAPLINC [ 42 ], SNHG8 [ 43 ], SNHG16 [ 39 ], UFC1 [ 32 ], AFAP1-AS1 [ 39 ], BCAR4 [ 40 ], CCAT2 [ 39 ], CRNDE [ 44 ], DLX6-AS1 [ 32 ], HNF1A-AS1 [ 45 ], HOXA-AS2 [ 44 ], NNT-AS1 [ 41 ], PCA3 [ 44 ], PCAT1 [ 46 ], SBF2-AS1 [ 39 ], SNHG11 [ 47 ], SNHG14 [ 48 ], SNHG6 [ 43 ], SNHG7 [ 49 ], and SOX2-OT [ 41 ] are predicted to sponge several miRNAs (in cancer cells) to promote cancer proliferation. Furthermore, LNCARSR [ 39 ] and LNCRNA-ATB [ 39 ] are predicted to sponge miRNA to promote the chemoresistance and migration of cancer.…”

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

“…And exosome-derived non-coding RNAs also play an important role in CRC. Lnc-PCAT1 from CRC exosomes can promote epithelial to mesenchymal transition (EMT) and liver metastasis in CRC by regulating the activity of the Netrin-1-CD146 complex in circulating tumor cells (CTCs) and thus provide a new molecular target for the treatment of liver metastasis in CRC ( 24 ). Circ_00016174 in Doxorubicin (DOX)-resistant CRC tissues and cells Levels are upregulated in circ_0006174-enriched exosomes that enhance DOX chemoresistance in CRC by regulating the miR-1205/cyclin D2 (CCND2) axis ( 25 ).…”