An NF90/long noncoding RNA-LET/miR-548k feedback amplification loop controls esophageal squamous cell carcinoma progression

Abstract

In our previous study we have found that miR-548k has oncogenic roles in esophageal squamous cell carcinoma (ESCC) via repressing long noncoding RNA (lncRNA)-LET and further upregulating nuclear factor 90 (NF90). However, the upstream factors controlling miR-548k expression are still unknown. In this study, we found NF90 directly binds pri-miR-548k, increases the stability of pri-miR-548k, and upregulates the expression of pri-miR-548k and miR-548k. Therefore, NF90, miR-548k and lncRNA-LET forms a feedback loop. Gain-of-function and loss-of-function assays demonstrated that in accordance with the roles of miR-548k, NF90 also promotes ESCC cell proliferation and migration. Furthermore, we verified the regulatory feedback loop between NF90, miR-548k, and lncRNA-LET. We found NF90 upregulated miR-548k and downregulated lncRNA-LET. miR-548k downregulated lncRNA-LET and upregulated NF90. lncRNA-LET downregulated NF90 and miR-548k. Through the reciprocal regulations between each other, the NF90/miR-548k/lncRNA-LET feedback loop controls the expressions of NF90 targets (HIF-1α and VEGF), miR-548k targets (KLF10 and EGFR), and lncRNA-LET target (p53). Further functional assays demonstrated that activation of the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously overexpressing NF90 and miR-548k and simultaneously depleting lncRNA-LET significantly promotes ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. Targeting the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously depleting NF90 and miR-548k and simultaneously overexpressing lncRNA-LET significantly inhibits ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. In summary, our findings identified a crucial oncogenic NF90/lncRNA-LET/miR-548k feedback amplification loop, which may be promising therapeutic targets for ESCC.

Recurrence-Associated Long Non-coding RNA LNAPPCC Facilitates Colon Cancer Progression via Forming a Positive Feedback Loop with PCDH7

“…Several feedback loops have been reported to be employed by cancer cells to exert their malignant behaviors, such as ERIC/E2F, miR-200a/HDAC4, SNHG14/ miR-5590-3p/ZEB1, NF90/lncRNA-LET/miR-548k, and so on. [52][53][54][55] Functional rescue experiments showed that inhibition of ERK activation or silencing of PCDH7 abrogated the oncogenic roles of LNAPPCC in colon cancer, which suggested that the LNAPPCC/ PCDH7/ERK/c-FOS feedback loop at least partially mediates the oncogenic roles of LNAPPCC in colon cancer.…”

The Polyvalent Role of NF90 in RNA Biology

“…In recent years, NF90 has been found to be differentially expressed in several types of cancers such as ovarian, breast, cervical, hepatocellular and nasopharyngeal carcinomas, leukemia, and bladder cancer [ 22 , 37 , 42 , 43 , 44 ]. While the impact of NF90 on cancer proliferation, progression, metastasis, and drug resistance is evident, its role in these processes is divergent and may depend on the cancer type.…”

“…On the other hand, NF90 can also bind and stabilize oncogenic pri-miRNAs such as pri-miR-548k, which is implicated in esophageal squamous cell carcinoma (ESCC), promoting cancer progression, metastasis, and poor overall survival [ 42 , 57 ]. Interestingly, miR-548k was shown to upregulate NF90 and downregulate lncRNA-LET, which acts as a tumor suppressor, establishing a feedback amplification loop that controls ESCC progression and metastasis [ 42 , 57 ].…”

lncRNA-LET Regulates Glycolysis and Glutamine Decomposition of Esophageal Squamous Cell Carcinoma Through miR-93-5p/miR-106b-5p/SOCS4

“…In another instance, the suppressors of cytokine signaling (SOCS-1 and SOCS-3) were revealed to be implicated in ESCC progression ( 19 ). Moreover, the association of lncRNA TUSC7, miR-616, and SOCS4 has been revealed in endometrial carcinoma ( 16 , 20 ). Notably, miR-1290 was abnormal in lung adenocarcinoma, contributing to cancer progression through targeting SOCS4 ( 21 ).…”

“…In general, lncRNAs serve as the spongers of microRNAs (miRNAs) that are abnormally expressed in various tumors ( 13 , 14 ), affecting other target genes via base pairing ( 15 ),—for instance, it was reported that the miR-548k in ESCC exerted oncogenic functions through downregulating the lncRNA-LET expression ( 16 ). On the contrary, upregulation of miR-93-5p and miR-106b-5p within esophageal carcinoma has been reported in the literature ( 17 , 18 ).…”