miR-330-5p targets SPRY2 to promote hepatocellular carcinoma progression via MAPK/ERK signaling

Abstract

MicroRNAs (miRNAs) have been identified as critical modulators of cell proliferation and growth, which are the major causes of cancer progression including hepatocellular carcinoma (HCC). Our previous miRNA microarray data have shown that miR-330-5p was always upregulated in HCC. However, the accurate role of miR-330-5p in HCC is still uncertain. Here, we report that miR-330-5p expression is upregulated in HCC tissues and cell lines, and is associated with tumor size, tumor nodule number, capsule formation and Tumor Node Metastasis (TNM) stage in HCC patients. Overexpression of miR-330-5p promotes proliferation and growth of HCC cells in vitro and in vivo, while miR-330-5p knockdown has the inverse effect. Moreover, using miRNA databases and dual luciferase report assay, we find miR-330-5p directly binds to the 3′-untranslated region (3′-UTR) of Sprouty2 (SPRY2). Then we find the novel biofunctional role of SPRY2 inactivation in promoting HCC progression. Finally, we confirm that miR-330-5p suppresses SPRY2 to promote proliferation via mitogen-activated protein kinases (MAPK)/extracellular regulated kinase (ERK) signaling in HCC. Taken together, our findings demonstrate the critical role of miR-330-5p in promoting HCC progression via targeting SPRY2 to activate MAPK/ERK signaling, which may provide a novel and promising prognostic marker and therapeutic target for HCC.

The Sprouty/Spred family as tumor suppressors: Coming of age

“…However, in testicular germ cell tumors, both Sprouty4 and SPRY4‐IT were found to function as oncogenes through activation of the PI3K‐Akt pathway . Moreover, miR‐122, miR‐27a, and miR‐330‐5p target Sprouty2, leading to enhanced cell proliferation . MicroRNA‐31 targets several negative regulators of the Ras/Raf/ERK pathway, including Sprouty1/3/4 and Spred1/2 .…”

“…18 Moreover, miR-122, miR-27a, and miR-330-5p target Sprouty2, leading to enhanced cell proliferation. [19][20][21] MicroRNA-31 targets several negative regulators of the Ras/Raf/ERK pathway, including Sprouty1/3/4 and Spred1/2. 22 The stability of Sprouty2 protein is regulated by several E3 ubiquitinprotein ligases, such as c-Cbl, Siah2, Nedd4-1, and pVHL, 2 although it is unknown how the stability of other Sprouty proteins is regulated.…”

<p>microRNA-548b suppresses aggressive phenotypes of hepatocellular carcinoma by directly targeting high-mobility group box 1 mRNA</p>

“…[11][12][13] A growing body of experimental evidence suggests that miRNAs can exert oncogenic or tumor-suppressive actions in HCC and can regulate a wide range of biological phenomena, such as cell proliferation, apoptosis, cell cycle, metastasis, epithelial-mesenchymal transition, and chemoresistance. [14][15][16] Thus, miRNAs may be promising targets for noninvasive treatment of HCC.…”

Clinical value of LHPP‐associated microRNAs combined with protein induced by vitamin K deficiency or antagonist‐II in the diagnosis of alpha‐fetoprotein‐negative hepatocellular carcinoma

“…Recent studies have found that many miRs are involved in the development of tumors, and their tissue and serological levels can be used as diagnostic markers for tumors. MiR can be used as a tumor marker based on the following: (a) It is stable in blood and tissues, and the detection method is relatively convenient and convenient and meets the conditions as a tumor marker; (b) it has the stage specificity of tumorigenesis, and the same tumor has different miR expression profiles in different stages of tumor development; and (c) it participates in all stages of tumorigenesis, development, and metastasis . Comparing the expression levels of tumor cells with normal cells, the miR expression profiles of the two were significantly different and could be released into the peripheral blood circulation and detected differences.…”