Long noncoding RNA NNT-AS1 enhances the malignant phenotype of bladder cancer by acting as a competing endogenous RNA on microRNA-496 thereby increasing HMGB1 expression

Abstract

The long noncoding RNA nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) is a key malignancy regulator in a variety of human cancers. In this study, we first measured the expression of NNT-AS1 in bladder cancer and examined its role in cancer progression. The mechanisms behind the oncogenic functions of NNT-AS1 in bladder cancer were explored. We found that NNT-AS1 was upregulated in bladder cancer tissues and cell lines. This increased expression demonstrated a significant correlation with advanced clinical stage, lymph node metastasis, and shorter overall survival. NNT-AS1 knockdown suppressed bladder cancer cell proliferation, migration, and invasion and facilitated apoptosis in vitro and hindered tumor growth in vivo. NNT-AS1 functioned as a competing endogenous RNA for microRNA-496 (miR-496), and the suppressive effects of NNT-AS1 knockdown on malignant characteristics were abrogated by miR-496 silencing. HMGB1 was identified as a direct target gene of miR-496 in bladder cancer, and HMGB1 expression was enhanced by NNT-AS1 via sponging of miR-496. In conclusion, the NNT-AS1-miR-496-HMGB1 pathway plays a significant role in the aggressive behavior of bladder cancer and may lead to new NNT-AS1-based diagnostics and therapeutics.

The Role of Long Non-Coding RNA NNT-AS1 in Neoplastic Disease

“…Many studies have found that the expression level of NNT-AS1 is related to the prognosis of tumor patients. Studies on NSCLC [17], gastric cancer [32], HCC [21], cervical cancer [25,26], and bladder cancer [30] have shown that high-levels of NNT-AS1 were poor prognostic factors to reduce overall survival (OS). In addition, for CAA and osteosarcoma, up-regulated NNT-AS1 was reported to be significantly associated with reduced OS and disease-free survival (DFS) [22,24,27].…”

“…In bladder cancer, NNT-AS1 can serve as the ceRNA of miR-496 and increase the expression of the downstream gene HMGB1 [30]. In breast cancer, NNT-AS1 inhibits miR-142-3p competitively, thereby promoting the expression of ZEB1, which in turn induces the proliferation and metastasis of cancer cells [36].…”

“…Current research shows that NNT-AS1 is highly expressed in most tumors, including non-small-cell lung cancer (NSCLC) [ 16 , 17 , 18 , 19 ], lung squamous cell carcinoma (LUSC) [ 20 ], colorectal cancer (CRC) [ 14 ], hepatocellular carcinoma (HCC) [ 21 ], cholangiocarcinoma (CAA) [ 22 , 23 , 24 ], cervical cancer [ 25 , 26 ], osteosarcoma [ 27 , 28 ], bladder cancer [ 29 , 30 ], and glioma [ 31 ]. These results have been verified in the corresponding tumor tissues or tumor cells.…”

Upregulated Expression of LncRNA Nicotinamide Nucleotide Transhydrogenase Antisense RNA 1 is Correlated with Unfavorable Clinical Outcomes in Cancers

“…Moreover, other pathways including PI3K/Akt/mTOR and Wnt/β-catenin signaling pathway were also found involved in the tumorigenesis and progression [26,15]. Besides, NNT-AS1 was capable of serving as a competing endogenous RNA (ceRNA) by sponging miR-485/BCL9 or miR-203 in cholangiocarcinoma [31,32], miR-1301-3p/PODXL or miR-496/HMGB1 in bladder cancer [3,33], miR-142-3p/ZEB1 in breast cancer [19], miR-424/E2F1 or miR-363 in gastric cancer [28,8], miR-22-3p/YAP1 or miR-129-5p in non-small cell lung cancer [34,30], and miR-320a in osteosarcoma [27], therefore alteration in cancer cell function resulting from NNT-AS1 downregulation may be rescued by miRNA inhibition. Notably, NNT-AS1 also showed a high expression level in drug-resistant NSCLC, which promoted the cisplatin resistance of cancer cells via the MAPK/Slug pathway [35].…”

Roles of HMGB1 in regulating myeloid-derived suppressor cells in the tumor microenvironment

“…The alarmin HMGB1 is released by most types of tumor cells and is detected in the serum of many cancer patients [40][41][42][43][44]. HMGB1 is ubiquitous in the TME and can interact with a variety of inflammatory cells to produce different results.…”