MicroRNA‐93‐5p expression in tumor tissue and its tumor suppressor function via targeting programmed death ligand‐1 in colorectal cancer

Abstract

This work aimed to investigate miR-93-5p expression in tumor tissue and its in vitro effects in colorectal cancer (CRC) by targeting programmed death ligand-1 (PD-L1). MiR-93-5p and PD-L1 expression was detected in CRC and adjacent normal tissues by quantitative real-time polymerase chain reaction and immunohistochemistry. The correlation between miR-93-5p and PD-L1 was validated by a dual-luciferase reporter assay. HCT116 and SW480 cells were divided into blank, miR-NC, miR-93-5p mimics, miR-93-5p inhibitor, PD-L1 small interfering RNA (siRNA) and miR-93-5p inhibitor + PD-L1 siRNA groups, and wound-healing and transwell assays were performed to detect cell migration and invasion, respectively. Protein expression was measured by western blotting. The secretion of cytokines was detected in the CRC cell/T coculture models. MiR-93-5p was downregulated in CRC tissues with upregulated PD-L1. In PD-L1-negative patients, miR-93-5p expression was increased compared with that in PD-L1-positive patients. MiR-93-5p and PD-L1 expression levels were associated with the tumor differentiation, lymphatic metastasis, TNM, Duke's stage, and prognosis of CRC. PD-L1 siRNA weakened the migration and invasion abilities via decreased expression of matrix metalloproteinase-1 (MMP-1), -2, and -9, and these effects were abolished by the miR-93-5p inhibitor. Additionally, anti-PD-L1 upregulated the expressions of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon γ (IFN-γ) in the coculture of T cells with CRC cells, but downregulated the expressions of IL-1β, IL-10, and TGF-β. However, these changes were partially reversed by miR-93-5p inhibition. miR-93-5p is expected to be a novel target for CRC treatment since it decreases the migration and invasion, as well as the immune evasion, of CRC cells via targeting PD-L1. Abbreviations: CRC, colorectal cancer; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin; ITIM, immunoreceptor tyrosinebased inhibitory motif; miRNA, microRNA; PD-L1, programmed death ligand-1 Role of miR-93-5p in CRC via targeting PD-L1Y.-L. Chen et al.

Downregulating Long Non-coding RNAs CTBP1-AS2 Inhibits Colorectal Cancer Development by Modulating the miR-93-5p/TGF-β/SMAD2/3 Pathway

“…These studies fully confirm that miRNA functions in CRC growth diversely, both as a carcinogenic and anticancer molecule. In previous studies, miR-93-5p showed a bidirectional effect in CRC progression, either by inhibiting PD-L1 from weakening CRC cell transfer (11) or by inhibiting cyclin-dependent kinase inhibitor 1A from enhancing the multidrug resistance of CRC cells (26). In the present study, we proved that miR-93-5p is a competitive miRNA of CTBP1-AS2 and is limited by the upregulated CTBP1-AS2.…”

“…Various studies have discovered that miRNAs regulate tumor growth (9). As a miRNA, miR-93-5p inhibits the Hippo signaling pathway, thus promoting gastric cancer cell process (10), and its knockdown inhibits CRC cell proliferation and metastasis by targeting programmed death ligand 1 (PD-L1) (11). Functionally, miRNAs are competitively inhibited by lncRNAs, on the other hand, it binds to the 3 ′ untranslated region (3 ′ -UTR) of mRNAs.…”

MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis

“…Likewise, epigenetic control of PD-L1 via DNA methyltransferase 1 notably influenced the response to chemotherapy (Huang et al, 2020). PD-L1 expression in CRC tissues was remarkably enhanced versus tumor-adjacent normal tissues, displaying a tight correlation to the differentiation and lymphatic metastasis of CRC patients (Chen et al, 2020). More significantly, the induction of immune checkpoints by malignancies can produce an immunosuppressive microenvironment, among which PD-L1 represents itself as the most frequently studied checkpoint (Payandeh et al, 2020).…”

HOXD Antisense Growth-Associated Long Noncoding RNA Promotes Triple-Negative Breast Cancer Progression by Activating Wnt Signaling Pathway

“…Furthermore, we found that miR-93-5p could bind to HAGLR and that SRSF1 was targeted by miR-93-5p in TNBC cells. Though miR-93-5p appears to play different roles—either oncogenic or tumor-suppressive—in different cancer types [ 15 29 ], its tumor-restraining function in breast cancers, including TNBC, has already been revealed [ 16 17 ]. In addition, consistent with the findings of previous studies [ 30 ], SRSF1 was upregulated in TNBC cells and exerted a tumor-promoting function in TNBC.…”

“…In the present study, miR-93-5p was selected as a HAGLR-interacting miRNA. miR-93-5p may play tumor-suppressing roles in colorectal cancer [ 15 ] and may be an effective tumor inhibitor in breast cancers [ 16 ], including TNBC [ 17 ]. However, the interplay between HAGLR and miR-93-5p has not yet, to our knowledge, been explored in cancer cells, let alone the influence of their interaction on TNBC progression.…”