Hypoxia-induced shedding of MICA and HIF1A-mediated immune escape of pancreatic cancer cells from NK cells: role of circ_0000977/miR-153 axis

Abstract

One key to malignant progression of pancreatic cancer (PC) is the acquired ability of tumour cells to escape immune-mediated lysis. Hypoxic microenvironment plays a causal role in PC metastasis. According to previous studies, hypoxia could induce the upregulation of HIF1A, ADAM10 and sMICA, leading to decreased NKG2D in NK cells and tumour cells escape from immune surveillance and NK cellmediated lysis. In the present study, in NK cells derived from high-HIF1A expression patients, the levels of internalization of MICA/B and NKG2D were obviously higher than those in low-HIF1A expression group; hypoxia dramatically upregulated the levels of sMICA culture supernatant of Panc-1 cells. Regarding the molecular mechanism, dysregulated circRNAs and miRNAs that might modulate HIF1Amediated immune escape were selected and examined for detailed functions. The expression of circ_0000977 could be induced by hypoxia, and circ_0000977 knockdown enhanced the killing effect of NK cells on PC cells under hypoxia through HIF1A and ADAM10. HIF1 and ADAM10 were direct downstream targets of miR-153; circ_0000977 served as a sponge for miR-153 to counteract miR-153mediated repression of HIF1 and ADAM10 mRNA through direct targeting in both 293T cells and Panc-1 cells. miR-153 inhibition exerted an opposing effect on HIF1A-mediated immune escape of PC cells to circ_0000977 knockdown; the effect of circ_0000977 knockdown were partially attenuated by miR-153 inhibition. In summary, circ_0000977/miR-153 axis modulates HIF1A-mediated immune escape of PC cells through miR-153 downstream targets HIF1A and ADAM10. We provided a novel mechanism of HIF1A-mediated immune escape of PC cells from the perspective of circRNAs-miRNA-mRNA axis. Abbreviations: Pancreatic cancer (PC); peripheral blood lymphocytes (PBLs); A Disintegrin and Metalloproteinase Domain 10 (ADAM10); MHC class I-related molecule A (MICA); soluble MICA (sMICA); membrane MICA (mMICA); Hypoxia-inducible factor 1-alpha (HI1FA); long non-coding RNAs (lncRNAs); non-coding RNAs (ncRNAs); natural killer (NK); Haematoxylin and eosin (H&E); Immunohistochemistry (IHC); natural killer group 2 member D (NKG2D);

The role of cancer-derived microRNAs in cancer immune escape

“…In pancreatic cancer cells, hypoxiaassociated pathways conspicuously downregulated membrane MICA while simultaneously increased sMICA expression [84]. This hypoxia-induced sMICA upregulation was attributed to the dysregulated balance between circ_0000977 and miR-153 [84].…”

“…Ovarian cancer [74] Hepatocellular carcinoma [75,76] Breast cancer [77] Colorectal cancer [78] Gastric cancer [79] miR-93 Hepatocellular carcinoma [76,80] miR-106b Hepatocellular carcinoma [76,80] miR-106a Hepatocellular carcinoma [75] miR-519a-3p Breast cancer [81] miR-125b a Multiple myeloma [82] miR-373 Hepatocellular carcinoma [75] miR-302c Multiple cancers [83] miR-520c Multiple cancers [83] miR-153 b Pancreatic cancer [84] MICB miR-20a Breast cancer [77] Hepatocellular carcinoma [75] miR-373 Hepatocellular carcinoma [75] miR-29a/b/c Hepatocellular carcinoma [75] miR-15b Hepatocellular carcinoma [75] miR-195 Hepatocellular carcinoma [75] miR-16 Hepatocellular carcinoma [75] miR-424 Hepatocellular carcinoma [75] miR-106a Hepatocellular carcinoma [75] miR-107 Hepatocellular carcinoma [75] miR-17 Hepatocellular carcinoma [75] miR-302c Multiple cancers [83] miR-520c Multiple cancers [83] ULBP miR-20a Breast cancer [77] miR-519a-3p Breast cancer [81] miR-302c Multiple cancers [83] miR-520c Multiple cancers [83] MICA (BET) inhibitor could remarkably increase MICA expression on multiple myeloma cells [82]. This BETiinduced MICA elevation was mediated by miR-125b, which targeted the transcription suppressor of MICA (IRF4) [82].…”

“…On the contrary to MICA expressed on cancer cells (also known as membrane MICA), soluble MICA (sMICA) is an unfavorable factor for anti-cancer immunity [84]. In pancreatic cancer cells, hypoxiaassociated pathways conspicuously downregulated membrane MICA while simultaneously increased sMICA expression [84]. This hypoxia-induced sMICA upregulation was attributed to the dysregulated balance between circ_0000977 and miR-153 [84].…”

Circular RNAs in the tumour microenvironment

“…Su et al further showed that circ-DENND2A was dramatically increased in glioma tissues with high level of HIF1α [55]. Moreover, another study showed that the circ-0000977 level can be induced by hypoxia in pancreatic cancer cells [140]. The axis of circ-0000977/miR-153 can mediate HIF1α-induced immune escape of pancreatic cancer cells through targeting HIF1α/ ADAM10 [140].…”

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

“…In addition, we identified transcriptional programs correlated with the non-T cell-inflamed phenotype such as KLF4, HIF1A, KMT2D (alias MLL2), NFE2L2 (alias NRF2), androgen receptor (AR), and estrogen receptor (ER) signaling, which have some literature support for modulating the immune response (Rizvi ;Kovats 2015;Ou et al 2019).…”