Long non-coding RNA GAS5 promotes natural killer cell cytotoxicity against gastric cancer by regulating miR-18a

Abstract

Natural killer (NK) cells play significant roles in spontaneous antitumor response in multiple cancers, including gastric cancer. Currently, lncRNAs were identified as essential modulators in the development of NK cells via competing for the target miRNA. However, the regulatory mechanism of GAS5 in NK cells remains largely elusive. The expressions of GAS5 and miR-18a in NK cells were measured by qRT-PCR. The killing effects of NK cells were conducted by lactate dehydrogenase (LDH) assay. Detection of IFN-γ and TNF-α level was carried out using ELISA assay. The interaction between GAS5 and miR-18a was determined by the luciferase reporter system and RIP assay, respectively. We found that GAS5 expression was downregulated while miR-18a expression was upregulated in primary NK cells isolated from GC patient compared with the healthy controls. Moreover, activation of NK cells stimulated by IL-2 enhanced the secretion of IFN-γ, TNF-α, and the expression of GAS5. The deficiency of GAS5 significantly suppressed the secretion of IFN-γ and TNF-α as well as the killing effect of NK cells. Subsequently, luciferase reporter and RIP assay confirmed the interaction between GAS5 and miR-18a. In addition, miR-18a inhibitor attenuated GAS5 silencing induced inhibition of the cytotoxicity of activated NK cells. In conclusion, GAS5 promotes the killing effect of the natural killer cells against GC by regulating miR-18a, providing promising strategies for NK cells based antitumor therapies.

Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential

“…The expression of the NK-specific lncRNA, lnc-CD56, was found to be a positive regulator of CD56 ( 104 ). In addition, the lncRNA, GAS5, could regulate the killing effect of NK cells in several types of cancer ( 105 , 106 ). These results demonstrate the importance of lncRNAs in NK cell function and the antitumor immune response.…”

The Non-Coding RNA GAS5 and Its Role in Tumor Therapy-Induced Resistance

“…In gastric cancer, three miRNAs have been reported to relate to GAS5 , miR-18a [ 95 ], miR-106a-5p [ 63 ] and miR-222 [ 96 ]. In the case of miR-18a, it was reported that GAS5 directly binds to it, inhibiting tumor growth via the stimulation of the activity of natural killer (NK) cells [ 95 ]. On the other hand, GAS5 functions as sponge for miR-106a-5p, inactivating the Akt/mTOR pathway [ 63 ].…”

“…In the case of miR-544, GAS5 negatively regulates its expression, inhibiting tumor cell proliferation [ 102 ]. GAS5 inhibits cell proliferation also through the miR-544/RUNX3 pathway [ 102 ], where it stimulates NK cell activity and inhibits tumor growth [ 95 ]. In addition, GAS5 and miR-135b reversely correlated and as reported in other tumors, GAS5 over-expression reduces miR-135b expression and, thus, inhibits tumor cell proliferation [ 103 ].…”

Long noncoding RNA: a dazzling dancer in tumor immune microenvironment

“…The expression of GAS5 augment NK cell cytotoxicity, IFN-γ secretion, and the proportion of CD107a + NK cells by sponging miR-544 to target RUNX3, and thus strengthening the killing effect of NK cells [ 108 ]. Furthermore, lncRNA GAS5 also potentiates the secretion of IFN-γ, TNF-α, as well as cytotoxicity of NK cells against gastric cancer via modulating miR-18a [ 107 ]. Notably, tumor-derived exosomes contain functional lncRNAs can be taken in NK cells for intercellular communication.…”