SNHG16 as the miRNA let‐7b‐5p sponge facilitates the G2/M and epithelial‐mesenchymal transition by regulating CDC25B and HMGA2 expression in hepatocellular carcinoma

Abstract

Long noncoding RNAs (lncRNAs) play crucial roles in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of small nucleolar RNA host gene 16 (SNHG16) for regulating the cell cycle and epithelial to mesenchymal transition (EMT) remain elusive. In this study, SNHG16 expression profiles of HCC tissues or cell lines were compared with those of normal tissues or hepatocyte cell line. The effect of SNHG16 knockdown in HCC cell lines was investigated by using in vitro loss-of-function experiments and in vivo nude mouse experiments. The potential molecular regulatory mechanism of SNHG16 in HCC progression was investigated by using mechanistic experiments and rescue assays. The results revealed that SNHG16 was highly expressed in HCC tissues and cell lines, which predicted poor prognosis of HCC patients. On one hand, the downregulation of SNHG16 induced G2/M cell cycle arrest, inducing cell apoptosis and suppression of cell proliferation. On the other hand, it inhibited cell metastasis and EMT progression demonstrated by in vitro loss-of-function cell experiments. Besides, knockdown of SNHG16 increased the sensitivity of HCC cells to cisplatin. For the detailed mechanism, SNHG16 was demonstrated to act as a let-7b-5p sponge in HCC. SNHG16 facilitated the G2/M cell cycle transition by directly acting on the let-7b-5p/CDC25B/CDK1 axis, and promoted cell metastasis and EMT progression by regulating the let-7b-5p/HMGA2 axis in HCC. In addition, the mechanism of SNHG16 for regulating HCC cell proliferation and metastasis was further confirmed in vivo by mouse experiments. Furthermore, these results can Shengguang Li and Fujun Peng contributed equally to this work.

P300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma

“…Certainly, we cannot rule out other mechanisms are involved in the regulation of HMGA2 expression in HCC. In fact, several long noncoding RNAs (lncRNAs), such as HULC, LSINCT5, LINC00473, SNHG16 and EGOT, have been found to promote HMGA2 expression in HCC [11,[34][35][36][37]. In addition, a series of microRNAs (miRs or miRNAs)…”

“…A large number of studies have shown that HMGA2 is highly expressed in most malignant tumors, and its expression level is closely related to the degree of malignancy and metastasis, including breast, melanoma, colorectal and bladder cancer [8,9]. More important, accumulating evidence have shown that HMGA2 is highly expressed in hepatocellular carcinoma, and the elevated HMGA2 predicts high incidence of metastasis and poor patient survival in hepatocellular carcinoma [10,11]. For example, overexpression of HMGA2 is an important contributor to the invasion of hepatocellular carcinoma cells, while HMGA2 knockdown impaired the migratory capacity of tumor cells in hepatocellular carcinoma [12,13].…”

LncRNA SNHG16 as a potential biomarker and therapeutic target in human cancers

“…SNHG16 contributes to chemoresistance in hepatocellular carcinoma. It was shown that siRNA knockdown of SNHG16 reverses sorafenib resistance in Hep3B and HepG2 cell lines [45], and sh-SNHG16 knockdown increases HuH7 and Hep3B cell sensitivities to cisplatin [47], but the underlying mechanisms were not clarified by these two studies. However, another study reported that upregulation of SNHG16 inhibits 5-fluorouracil (5-FU) chemoresistance in Hep3B and HuH7 cells [44], which contrasts the two reports mentioned above.…”

“…In addition, there are some molecules reported to be mediated by SNHG16, including Stearoyl-CoA Acute Lymphoblastic Leukemia MOLT3 BALB/c nude mice promote [22] Cervical cancer HeLa BALB/c nude mice promote [29] Colorectal cancer LoVo BALB/c nude mice promote [30] Diffuse large B-cell lymphoma OCI-LY7 NOD/SCID mice promote [33] Esophageal squamous cell carcinoma kyse-70 BALB/c nude mice promote [35] Gastric cancer MGC-803 BALB/c nude mice promote [38] Hepatocellular carcinoma HuH7 athymic nude mice inhibit [44] HuH7 BALB/c nude mice promote [47] HepG2 BALB/c nude mice promote [48] HepG2 athymic nude mice promote [49] Hep-3B BALB/c nude mice promote [50] Neuroblastoma SK-N-SH BALB/c nude mice promote [51] Non small cell lung cancer A549 BALB/c nude mice promote [53,54] Oral squamous cell carcinoma TSCCA BALB/c nude mice promote [55] Pancreatic cancer AsPC-1 BALB/c nude mice promote [61] Retinoblastoma Y79 BALB/c nude mice promote [63] Desaturase (SCD) [31], p-AKT and matrix metallopeptidase 9 (MMP9) [60], Dickkopf-related protein 3 (DKK3) [39], and Wnt/β-catenin [36], but the underlying regulate mechanisms are not well uncovered. Furthermore, whether SNHG16 has other regulatory functions still needs further investigation.…”

“…The corresponding AUC values for the lncRNA combination in Ta, T1, and T2-T4 cases were 0.760, 0.827, and 0.878, respectively. In the validation cohort, an AUC for the three-lncRNA combination of 0.826 was obtained, and sensitivity and specificity were let-7b-5p luciferase reporter assay, RIP CDC25B/CDK1 hepatocellular carcinoma [47] miR-124-3p luciferase reporter assay acute Lymphoblastic Leukemia [22] miR-128-3p luciferase reporter assay, RIP HOXA7 neuroblastoma [51] miR-1301 luciferase reporter assay, RNA pull down BCL9 osteosarcoma [59] miR-135a luciferase reporter assay, RIP JAK2/STAT3 gastric Cancer [37] miR-140-5p luciferase reporter assay, RIP, RNA pull down ZEB1 esophageal squamous cell carcinoma [35] luciferase reporter assay, RIP retinoblastoma [63] miR-146a luciferase reporter assay, RIP MUC5AC non small cell lung cancer [53] miR-17-5p luciferase reporter assay TIMP3 bladder cancer [23] luciferase reporter assay, RIP p62 hepatocellular carcinoma [49] miR-186 luciferase reporter assay hepatocellular Carcinoma [50] miR-195 luciferase reporter assay, RIP hepatocellular carcinoma [48] miR-200a-3p luciferase reporter assay colorectal cancer [30] miR-205 ZEB1 osteosarcoma [58] miR-216-5p luciferase reporter assay, RIP, RNA pull down ZEB1 cervical cancer [28] miR-218-5p luciferase reporter assay, RNA pull-down HMGB1 pancreatic cancer [61] miR-302a-3p luciferase reporter assay, RNA pull-down FGF19 hepatocellular carcinoma [46] miR-340 luciferase reporter assay osteosarcoma [56] miR-373 luciferase reporter assay EGFR glioma [43] miR-4518 luciferase reporter assay PRMT5 glioma [41] miR-490-3p luciferase reporter assay HK2 endometrial carcinoma [34] miR-497 luciferase reporter assay BDN, YAP1 papillary thyroid cancer [62] miR-497-5p luciferase reporter assay, RIP, RNA pull down PIM1 diffuse large B-cell lymphoma [33] miR-520a-3p luciferase reporter assay EphA2 non small cell lung cancer [54] miR-628 luciferase reporter assay gastric cancer [40] miR-93 luciferase reporter assay hepatocellular carcinoma [44] miR-98 luciferase reporter assay STAT3 bladder cancer [24] luciferase reporter...…”