<p>Circular RNA ITCH Suppresses Cell Proliferation but Induces Apoptosis in Oral Squamous Cell Carcinoma by Regulating miR-421/PDCD4 Axis</p>

Abstract

Background: Circular RNAs (circRNAs), a group of covalently closed non-coding RNAs, serve critical regulatory roles in many human cancers, including oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate the functional role of circular RNA ITCH (circ-ITCH) in OSCC and the underlying mechanisms. Methods: RT-qPCR analysis was applied to detect the expression levels of circ-ITCH in OSCC tissues and cell lines. MTT assay and flow cytometer analysis were used to evaluate the effects of circ-ITCH overexpression on the proliferation and apoptosis of OSCC cells. Bioinformatics analysis and dual-luciferase reporter assay were applied to determine the binding relation between circ-ITCH and miR-421 as well as PDCD4 mRNA and miR-421. Results: Our results showed that circ-ITCH expression was remarkably decreased in OSCC tissues and cell lines. Low circ-ITCH expression was strongly associated with adverse clinicopathological characteristics of OSCC patients. Moreover, functional assays demonstrated that circ-ITCH overexpression significantly inhibited OSCC cell proliferation and induced cell apoptosis. Our data further uncovered that circ-ITCH could bind directly to miR-421 and block its repression on PDCD4 in OSCC. MiR-421 expression was significantly increased in OSCC tissues and was inversely correlated with circ-ITCH expression. Notably, miR-421 restoration blocked the tumor-suppressive role of circ-ITCH in OSCC cells. Conclusion: In conclusion, our study reveals that circ-ITCH serves as a tumor suppressor in OSCC partly by regulating miR-421/PDCD4 axis.

The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

“…Upregulated circITCH enhanced the toxicity of chemotherapeutic agents against drug‐resistant multiple myeloma cells [ 68 ]. Similarly, the expression level of circITCH was reduced in OSCC tissues and cell lines compared to adjacent normal tissues and human oral keratinocytes, and circITCH overexpression significantly inhibited OSCC cell proliferation and induced apoptosis [ 69 ]. Therefore, it can be speculated that circRNA can also mediate the toxicity of chemotherapeutic drugs on OSCC cells.…”

Research Progress of circRNAs in Head and Neck Cancers

“…Multiple circRNAs have been demonstrated to be involved in HNC development through the regulation of the proliferation process ( Figure 1 ). CircATRNL1 ( 40 ), hsa_circ_0007059 ( 41 ), circRNA_002178 ( 42 ), hsa_circ_0046263 ( 43 ), hsa_circ_0005379 ( 44 ), circUHRF1 ( 45 ), circPVT1 ( 46 , 47 ), circHIPK3 ( 48 , 49 ), circRNA_0000140 ( 50 ), circRNA_100290 ( 51 ), circDOCK1 ( 52 ), hsa_circ_0055538 ( 53 ), circITCH ( 54 ), hsa_circRNA_101036 ( 55 ), circCCND1 ( 20 ), circMYLK ( 56 ), CDR1as ( 17 , 57 , 58 ), circPKD2 ( 59 ), circLARP4 ( 60 ), hsa_circ_0042666 ( 61 ), hsa_circRNA_100533 ( 62 ), circMDM2 ( 63 ), circ_0067934 ( 64 ), circRPMS1 ( 65 ), circ-ZNF609 ( 66 , 67 ), hsa_circ_0072387 ( 68 ), circRASSF2 ( 38 ), hsa_circ_0023028 ( 69 ), circCTDP1 ( 70 ), circ_0008450 ( 71 ), circMATR3 ( 72 ), hsa_circ_0057481 ( 73 ), circ_0001742 ( 74 ), circ_0000218 ( 75 ), circ_0001971 ( 76 ), circCORO1C ( 77 ), hsa_circ_0109291 ( 78 ), hsa_circ_0036722 ( 34 ), hsa_circ_0002203 ( 79 ) and hsa_circ_0066755 ( 80 ) are associated with tumor proliferation ( Table 1 ).…”

“…Studies have found that PDCD4 inhibits FLIP-mediated tumor cell apoptosis. In addition, circ-ITCH can directly bind to miR-421 and block its inhibition of PDCD4 in OSCC and induce cell apoptosis ( 54 ). Endoplasmic reticulum stress is another way to induce apoptosis.…”

Circular RNA ITCH Is a Tumor Suppressor in Clear Cell Renal Cell Carcinoma Metastasis through miR-106b-5p/PDCD4 Axis

“…So it is necessary for RCC to find new circRNAs target. Among these circRNAs, circular RNA ITCH (circ-ITCH) acts as a tumor suppressor in the occurrence of several tumors, such as hepatocellular carcinoma [ 22 ], ovarian cancer [ 23 ], oral squamous cell carcinoma [ 24 ], cervical cancer [ 25 ], osteosarcoma [ 26 ], and prostate cancer [ 27 ]. But the role of circ-ITCH in ccRCC is not clarified now.…”