circ-Keratin 6c Promotes Malignant Progression and Immune Evasion of Colorectal Cancer through microRNA-485-3p/Programmed Cell Death Receptor Ligand 1 Axis

Abstract

Background: Recently, circular RNA (circRNA) was reported to be a significant participant in the development of tumorigenesis, including colorectal cancer. Therefore, we aimed to clarify the precise role of circ-keratin 6C (circ-KRT6C) in colorectal cancer progression. Methods: The relative expression levels of circ-KRT6C, microRNA-16-5p (miR-485-3p), and programmed cell death receptor ligand 1 (PDL1) were analyzed by real-time quantitative polymerase chain reaction and western blot assays. The proliferation was assessed by cell count kit 8 and colony-forming assays. The apoptotic cells were determined by flow cytometry assay. The migration and invasion were analyzed by transwell assay. Colorectal cancer cells were co-cultured with peripheral blood mononuclear cells or cytokine-induced killer cells to assess immune response. The interaction relationships among circ-KRT6C, miR-485-3p, and PDL1 were examined by dual-luciferase reporter assay. The effects of circ-KRT6C inhibition in vivo was analyzed by an animal experiment. Results: Circ-KRT6C was overexpressed in colorectal cancer tissues and cells, and its level was associated with overall survival time of colorectal cancer patients. The suppression of circ-KRT6C suppressed growth, migration, invasion, and immune escape while stimulated apoptosis in colorectal cancer cells, which was abolished by shortage of miR-485-3p. In addition, overexpression of miR-485-3p repressed malignant progression and immune evasion of colorectal cancer by targeting PDL1, implying that PDL1 was a functional target of miR-485-3p. A xenograft experiment also suggested that circ-KRT6C inhibition could repress tumor growth in vivo. Conclusion: Circ-KRT6C could increase PDL1 expression by functioning as a miR-485-3p sponge, which promoted malignant progression and immune evasion of colorectal cancer cells.

Circular RNA hsa_circ_0000190 Facilitates the Tumorigenesis and Immune Evasion by Upregulating the Expression of Soluble PD-L1 in Non-Small-Cell Lung Cancer

“…For evaluation of the association between immune checkpoints and hsa_circ_0000190, relevant ligands were selected, such as CD80/CD86, which interacted with CTLA-4 and CD28 for T-cell inhibition or activation, respectively. The other immune checkpoints included TIM-3, BTLA, TIGIT, LAG-3, and PD-1, and the related binding partners were galectin-9, HVEM, PVR (CD155), HLA-DR, and PD-L1, respectively [ 13 , 14 , 15 , 16 , 17 ].…”

“…Multiple studies have reported the role of circRNAs in regulating the expression of PD-L1 through circRNA–miRNA–mRNA axis. A number of circRNAs, such as circBART2.2, hsa_circ_0136666, circ-keratin 6c, CDR1-AS, circ-VIM, hsa_circ_0003288, CircCHST15, circ-CPA4, hsa-circRNA-002178, and Circ_0000284 were shown to affect PD-L1 expression, leading to tumor immune escape in various types of cancers, including nasopharyngeal carcinoma, colorectal cancer, esophageal cancer, hepatocellular carcinomas (HCC), and lung cancer [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Our previous study discovered the correlation between hsa_circ_0000190 plasma level and PD-L1 level in patients with lung cancer.…”

Roles of circular RNAs in colorectal cancer (Review)

“…Emerging evidence has shown that utilization of immune checkpoints by cancer cells is important for immune evasion ( 85 ). Recently, Jiang et al ( 86 ) revealed the association between circRNAs and immune evasion in CRC. It was demonstrated that circ-keratin 6C (KRT6C), which is encoded from the KRT6C gene, functioned as a miR-485-3p sponge and promoted immune evasion by upregulating programmed cell death receptor ligand 1, which is the ligand for the immune check point programmed cell death protein 1 ( 86 ).…”

“…Recently, Jiang et al ( 86 ) revealed the association between circRNAs and immune evasion in CRC. It was demonstrated that circ-keratin 6C (KRT6C), which is encoded from the KRT6C gene, functioned as a miR-485-3p sponge and promoted immune evasion by upregulating programmed cell death receptor ligand 1, which is the ligand for the immune check point programmed cell death protein 1 ( 86 ). This suggests the possible role of circRNAs in immune regulation and immune evasion.…”

Circular RNA hsa_circ_0083756 promotes intervertebral disc degeneration by sponging miR‐558 and regulating TREM1 expression

“… 19 Consistently, circ‐KRT6C promoted malignant progression and immune evasion of colorectal cancer via acting as a miR‐485‐3p sponge. 21 Recently, increasing evidence has revealed that many circRNAs are also differently expressed between non‐degenerated and degenerated NP tissues, 22 indicating their potential functions in the development of IVDD. Although some circRNAs have been revealed diverse functions in the regulation of IVDD, 23 the role and underlying mechanisms of circRNAs in IVDD largely remain vague and need further investigation.…”