Noncoding RNA 886 alleviates tumor cellular immunological rejection in host C57BL/C mice

Abstract

Non‐coding RNA 886 (nc886/VTRNA2‐1) is a Pol III transcript and an atypical imprinted gene. Its exact function as a negative regulator of protein kinase R establishes its connection with innate immunity. Studies have shown that nc886 silencing is closely associated with prostate cancer progression. Previous work has constructed a cell model of stable nc886 overexpression (“mimic” or “nc886 + ”) in PC‐3M‐1E8 cell lines (1E8), which are highly bone‐metastatic human prostate cancer cells with low expression of nc886, and cells expressing the mimic were validated to have lower invasive and metastatic abilities than cells expressing the scramble transcript in vitro and in vivo. In this study, we directly injected mimic or scramble cells into the left ventricle of C57BL/C mice, an immunocompetent animal model, to elucidate the immune mechanisms of tumor‐host interactions. Interestingly, we found that tumor cells induced the inflammation of many important organs due to xenogeneic antigen rejection; this inflammation was ultimately repaired by tissue fibrosis after 28 days, except for in the spleen. The reason is that mimic cells, as heterogeneous antigens, are mostly directly recognized by macrophages or T cells in blood, and few mimic cells enter the spleen compared with scramble cells. The induction of splenic macrophage polarization to M2 macrophages by scramble cells is a critical factor in maintaining chronic splenic inflammation. In addition, we recognize that nc886 broadly decreases the expression of some human leukocyte antigen molecules and antigen transporters. This evidence reveals the interesting role of nc886 in regulating tumor cell antigens.

Pan-cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

“…This association agrees with its proposed roles in innate immune modulation via PKR repression or OAS1 regulation and in cytokine production (Calderon & Conn, 2018;Golec et al, 2019;Lee et al, 2020;Li et al, 2015). Furthermore, vtRNA2-1 has been associated with autoimmune disorders (Renauer et al, 2015;Weeding & Sawalha, 2018) and tumor engraftment in prostate cancer (Ma et al, 2020). This enrichment in viral infection pathways, together with the viral infection involvement of the core TFs common to all vtRNAs, reinforces the hypothesis of the re-utilization of a regulatory RNA induced upon viral response in favor of cancer development at upstream and downstream regulatory steps.…”

“…Due to its importance for cancer biology, vtRNA2-1 transcriptional regulation was recently more investigated (Yeganeh & Hernandez, 2020). Various studies reported tissue specific roles of vtRNA2-1 in normal (Golec et al, 2019;Lee et al, 2019;Miñones-Moyano et al, 2013;Sallustio et al, 2016;Suojalehto et al, 2014) and cancer tissues (Ahn et al, 2018;Fort et al, 2018;Hu et al, 2017;Im et al, 2020;Jeon et al, 2012a;Kunkeaw et al, 2012;Lee et al, 2011;Lee, 2015;Lee et al, 2014a;Lee et al, 2014b;Lee et al, 2016;Lei et al, 2017;Li et al, 2017;Ma et al, 2020;Treppendahl et al, 2012) and epigenetic alterations of the locus have been described in different malignancies (Ahn et al, 2018;Cao et al, 2013;Fort et al, 2018;Helbo et al, 2015;Helbo et al, 2017;Joo et al, 2018;Lee et al, 2014a;Lee et al, 2014b;Park et al, 2017a;Romanelli et al, 2014;Treppendahl et al, 2012). Meanwhile, except for Kirsten Grønbaek group´s contributions on the chromatin characterization of vtRNA1-3 and vtRNA1-2 promoters (Helbo et al, 2015;Helbo et al, 2017), little is known about the transcriptional regulation and expression of the other vtRNAs.…”

“…Although the same study demonstrated that vtRNA1-1 expression was unchanged during T cell activation, it is remarkable that the 5q31-q33 region, comprising the vtRNA1 locus and chromatin co-regulated genes, encodes several cytokines that regulate the differentiation of Th1 and Th2 lymphocytes and has been linked with susceptibility to infections (Jeronimo et al, 2007;Lacy et al, 2000;Naka et al, 2009;Rodrigues et al, 1999). Furthermore, vtRNA2-1 levels were recently associated with macrophages M1/M2 fates in prostate PC3 cell line mice xenografts via TGF-b (Ma et al, 2020), two pathways that define the six immune subtypes (Thorsson et al, 2018). Finally, we found that the proliferation rate and wound healing of the tumors are associated with the levels of vtRNA1-2 chromatin accessibility, which reinforces an OG role of vtRNA1-2 in cancer.…”

“…Moreover, vtRNA2-1 was proposed as a new type of ncRNA functioning as a tumor suppressor gene (TSG) that inhibits PKR, and was consequently renamed as "nc886" (Golec et al, 2019;Jeon et al, 2012a;Jeon et al, 2012b;Lee et al, 2011). Then, its anti-proliferative and TSG function was described in prostate (Aakula et al, 2016;Fort et al, 2018;Ma et al, 2020), skin (Lee et al, 2019a), gastric (Lee et al, 2014b) esophageal (Im et al, 2020;Lee et al, 2014a) and cholangiocarcinoma cells (Kunkeaw et al, 2012). Conversely, a pro-proliferative and anti-apoptotic oncogenic role was proposed for vtRNA2-1 in renal (Lei et al, 2017), ovarian (Ahn et al, 2018), thyroid (Lee et al, 2016), cervical (Li et al, 2017) and endometrial (Hu et al, 2017) tissues.…”

Pan-cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

“…Moreover, vtRNA2-1 was proposed as a new type of ncRNA functioning as a tumor suppressor gene (TSG) that inhibits PKR, and was consequently renamed as “nc886” ( Golec et al , 2019 ; Jeon et al , 2012a ; Jeon et al , 2012b ; Lee et al , 2011 ). Then, its anti-proliferative and TSG function was described in prostate ( Aakula et al , 2016 ; Fort et al , 2018 ; Ma et al , 2020 ), skin ( Lee et al , 2019a ), gastric ( Lee et al , 2014b ) esophageal ( Im et al , 2020 ; Lee et al , 2014a ) and cholangiocarcinoma cells ( Kunkeaw et al , 2012 ). Conversely, a pro-proliferative and anti-apoptotic oncogenic role was proposed for vtRNA2-1 in renal ( Lei et al , 2017 ), ovarian ( Ahn et al , 2018 ), thyroid ( Lee et al , 2016 ), cervical ( Li et al , 2017 ) and endometrial ( Hu et al , 2017 ) tissues.…”