STAT3-induced long noncoding RNAs in multiple myeloma cells display different properties in cancer

Abstract

Interleukin-6 (IL-6)-activated Signal Transducer and Activator of Transcription 3 (STAT3) facilitates survival in the multiple myeloma cell line INA-6 and therefore represents an oncogenic key player. However, the biological mechanisms are still not fully understood. In previous studies we identified microRNA-21 as a STAT3 target gene with strong anti-apoptotic potential, suggesting that noncoding RNAs have an impact on the pathogenesis of human multiple myeloma. Here, we describe five long noncoding RNAs (lncRNAs) induced by IL-6-activated STAT3, which we named STAiRs. While STAiRs 1, 2 and 6 remain unprocessed in the nucleus and show myeloma-specific expression, STAiRs 15 and 18 are spliced and broadly expressed. Especially STAiR2 and STAiR18 are promising candidates. STAiR2 originates from the first intron of a tumor suppressor gene. Our data support a mutually exclusive expression of either STAiR2 or the functional tumor suppressor in INA-6 cells and thus a contribution of STAiR2 to tumorigenesis. Furthermore, STAiR18 was shown to be overexpressed in every tested tumor entity, indicating its global role in tumor pathogenesis. Taken together, our study reveals a number of STAT3-induced lncRNAs suggesting that the interplay between the coding and noncoding worlds represents a fundamental principle of STAT3-driven cancer development in multiple myeloma and beyond.

Master and servant: LINC00152 – a STAT3-induced long noncoding RNA regulates STAT3 in a positive feedback in human multiple myeloma

“…This observation has since been confirmed by further publications [11][12][13]. Therefore, our preliminary data supported the view that STAiR18 contributes to STAT3-dependent tumorigenesis in multiple myeloma as well as in other cancer entities [8]. This observation has since been confirmed by further publications [11][12][13].…”

“…This observation has since been confirmed by further publications [11][12][13]. Therefore, our preliminary data supported the view that STAiR18 contributes to STAT3-dependent tumorigenesis in multiple myeloma as well as in other cancer entities [8]. In this study, we aimed to characterize the molecular function of STAiR18 in INA-6 cells in order to clarify whether it has an impact on myeloma cell survival.…”

“…Moreover, at the time we identified the STAiRs, STAiR15 (alias MIAT) was already described in great detail [9,10] in contrast to STAiR18. Most importantly, only STAiR18 showed a global overexpression in various cancer types [8]. This observation has since been confirmed by further publications [11][12][13].…”

“…Furthermore, in a genome-wide transcription study in INA-6 cells we demonstrated that in addition to proteincoding mRNAs, IL-6 regulates the transcription of a large number of long noncoding RNAs (lncRNAs) [7]. In a previous publication [8], we characterized five of these IL-6-induced lncRNAs (STAiR1, STAiR2, STAiR6, STAiR15 and STAiR18) in more detail, verifying them as STAT3 targets, and therefore named them STAT3induced ncRNAs (STAiRs). Out of this pool of STAiRs, we focused on STAiR18 for the following reasons: In contrast to the unprocessed macroRNAs STAiR1, − 2 and − 6, STAiR15 and − 18 were spliced and therefore suited better to carry out functional analyses by siRNAbased knockdown strategies.…”

The role of long non‐coding RNAs in multiple myeloma

“…STAT3-induced long non-coding RNAs (STAiRs) are induced by IL-6activated STAT3 in INA-6 MM cells, which include STAiR1, STAiR2, STAiR6, STAiR15, and STAiR18. 82 With length of its transcript ranging from 20 to 420 kb, they are located on different chromosomes.…”