Long non-coding RNA HOTTIP promotes renal cell carcinoma progression through the regulation of the miR-615/IGF-2 pathway

Abstract

Emerging evidence has indicated that long non‑coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) regulates cell growth, differentiation, apoptosis and cancer progression. However, the expression and function of HOTTIP in the progression of renal cell carcinoma (RCC) remain largely unknown. In this study, we investigated the role of the lncRNA HOTTIP in RCC. The expression levels of HOTTIP in RCC tissues and cell lines were determined by RT‑qPCR. The association between HOTTIP expression and clinicopathological characteristics and prognosis was analyzed in patients with RCC from the TCGA database. Loss‑of‑ function assays were designed and conducted to verify the oncogenic function of HOTTIP in RCC progression. Luciferase assay was performed to explore the mechanisms of the miRNA‑lncRNA sponge. The results revealed that HOTTIP expression was upregulated in RCC. An increased HOTTIP expression in RCC was associated with a larger tumor size and a higher clinical stage, lymph node metastasis and vascular invasion. Additionally, patients RCC with a high HOTTIP expression had a significantly shorter overall survival (OS) and disease‑free survival (DFS). HOTTIP knockdown significantly inhibited cell proliferation, migration and invasion, and increased the apoptosis of RCC cells in vitro. Mechanistic analyses revealed that HOTTIP functioned as a competing endogenous RNA (ceRNA) for hsa‑miR‑615‑3p, and led to the derepression of its endogenous target, insulin‑like growth factor-2 (IGF‑2), which is a protein hormone that exerts a stimulatory effect on tumor cell growth. miR‑615 inhibition reversed the suppressive effects of HOTTIP knockdown on RCC cell progression. HOTTIP regulated IGF‑2 expression in a miR‑615‑dependent manner in RCC cells. In addition, IGF‑2 expression was significantly upregulated in the RCC specimens and a positive association between the expression of HOTTIP and IGF‑2 in RCC tissues was detected. The effect of HOTTIP was abolished by the siRNA‑mediated silencing of IGF-2 in RCC cells. On the whole, this study demonstrates, for the first time, at least to the best of our knowledge, that the HOTTIP/miR‑615/IGF‑2 axis plays an important role in RCC progression and potentially contributes to the improvement of RCC diagnosis and therapy.

Circulating Non-coding RNAs in Renal Cell Carcinoma—Pathogenesis and Potential Implications as Clinical Biomarkers

“…Results in other cancer types suggest a tumor-suppressive role of let-7i as, for instance, they are downregulated in ovarian and bladder cancer and inhibited tumor proliferation and chemoresistance (Yang et al, 2008;Qin et al, 2019). As for miR-615-3p, Wang Q. et al (2018) found it to be sponged by the lncRNA HOXA transcript at the distal tip (HOTTIP) and to target insulin-like growth factor 2 in RCC. In their study, HOTTIP was shown to be upregulated in RCC tissue, and the overexpression of HOTTIP was reported to promote RCC proliferation, migration, and invasion in vitro, implicating a tumor-suppressive role of miR-615-3p (Wang Q. et al, 2018).…”

“…As for miR-615-3p, Wang Q. et al (2018) found it to be sponged by the lncRNA HOXA transcript at the distal tip (HOTTIP) and to target insulin-like growth factor 2 in RCC. In their study, HOTTIP was shown to be upregulated in RCC tissue, and the overexpression of HOTTIP was reported to promote RCC proliferation, migration, and invasion in vitro, implicating a tumor-suppressive role of miR-615-3p (Wang Q. et al, 2018). Chanudet et al (2017) screened for circulating miRNAs in RCC using microRNA arrays in plasma samples of 94 ccRCC patients of all clinical stages and 100 healthy controls.…”

MicroRNA‑615 functions as a tumor suppressor in osteosarcoma through the suppression of HK2

“…Moreover, overexpression of miR-615 was found to promote cell proliferation and migration and inhibit apoptosis in gastric cancer (10). However, downregulation of miR-615 was found in non-small cell lung cancer and renal cell carcinoma (11,12). In addition, miR-615 was found to play an inhibitory role in esophageal squamous cell carcinoma by targeting IGF2 (13).…”

LncRNA NBAT1 suppresses cell proliferation and migration via miR‐346/GSK‐3β axis in renal carcinoma

“…For example, MALAT1 directly targeted miR‐429 to improve the proliferation, migration, and invasion abilities of RCC cells . In addition, HOTTIP functioned as a ceRNA for miR‐615‐3p, antagonized its functions in RCC cells . Furthermore, lncRNA HOXA11‐AS positively regulated the expression of miR‐146b‐5p target gene MMP16 to promote the growth and invasion of RCC cells .…”