miR­653­5p suppresses the growth and migration of breast cancer cells by targeting MAPK6.

Breast cancer is the worldwide leading cause of cancer­related deaths among women. Increasing evidence has demonstrated that microRNAs (miRNAs) play critical roles in the carcinogenesis and progression of breast cancer. miR­653­5p was previously reported to be involved in cell proliferation and apoptosis. However, the role of miR­653­5p in the progression of breast cancer has not been studied. In the present study, it was found that overexpression of miR­653­5p significantly inhibited the proliferation, migration and invasion of breast cancer cells in vitro. Moreover, overexpression of miR­653­5p promoted cell apoptosis in breast cancer by regulating the Bcl­2/Bax axis and caspase­9 activation. Additionally, the epithelial­mesenchymal transition and activation of the Akt/mammalian target of rapamycin signaling pathway were also inhibited by miR­653­5p. Furthermore, the data demonstrated that miR­653­5p directly targeted mitogen­activated protein kinase 6 (MAPK6) and negatively regulated its expression in breast cancer cells. Upregulation of MAPK6 could overcome the inhibitory effects of miR­653­5p on cell proliferation and migration in breast cancer. In conclusion, this study suggested that miR­653­5p functions as a tumor suppressor by targeting MAPK6 in the progression of breast cancer, and it may be a potential target for breast cancer therapy.

Long non-coding RNA SNHG6 enhances cell proliferation, migration and invasion by regulating miR-26a-5p/MAPK6 in breast cancer.

The long non-coding RNA (lncRNA) has recently been shown to be important regulators involved in the progression of various human cancers. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA. However, the clinical significance and biological function of SNHG6 in breast cancer (BC) are still unclear. In the present study, we found that SNHG6 was highly expressed in BC tissues and cell lines, which was associated with poorer clinicopathologic features. Knockdown of SNHG6 inhibited BC cell proliferation, migration and invasion in vitro and in vivo using CCK-8, Edu staining, transwell assays and nude mice model. Moreover, bioinformatics analysis and luciferase reporter experiments indicated that SNHG6 serves as an endogenous sponge by directly binding to miR-26a-5p and down-regulating miR-26a-5p expression. MiR-26a-5p overexpression significantly enhanced the effect of SNHG6 knockdown on the cell behaviors in BC. Furthermore, bioinformatics analysis and luciferase reporter indicated that MAPK6 was validated as a target of miR-26a-5p. Therefore, our study may reveal a novel SNHG6/miR-26a-5p/MAPK6 pathway regulatory axis in BC pathogenesis. SNHG6 may serve as a potential prognostic and therapeutic target in the treatment of BC.

A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells.

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.

New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation.

The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.

Leptin activates human B cells to secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway.

Leptin, one of the adipokines, functions as a hormone and a cytokine. In this investigation, we show for the first time that leptin, in a concentration-dependent manner, activates human peripheral blood B cells to induce secretion of IL-6, IL-10, and TNF-α. Leptin increased B cells expressing CD25 and HLA-DR. Leptin induces phosphorylation of Janus activation kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase (ERK1/2). Furthermore, leptin-induced cytokine secretion by B cells was blocked by inhibitors of JAK2, STAT3, p38MAPK, and ERK1/2. These data demonstrate that leptin activates human B cells to secrete cytokines via activation of JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathways, which may contribute to its inflammatory and immunoregulatory properties.

Supraphysiologic extracellular pressure inhibits intestinal epithelial wound healing independently of luminal nutrient flow.

BACKGROUND: Luminal pressure may injure the gut mucosa in obstruction, ileus, or inflammatory bowel disease. METHODS: We formed Roux-en-Y anastomoses in 19 mice, creating proximal and defunctionalized partially obstructed limbs and a distal limb to vary luminal pressure and flow. We induced mucosal ulcers by serosal acetic acid, and assessed proliferation (proliferating cell nuclear antigen) and ERK (immunoblotting). Parallel studies compared Caco-2 enterocyte migration and proliferation after pressure and/or ERK blockade. RESULTS: At 3 days, anastomoses were probe-patent, proximal and distal limbs contained chyme, and defunctionalized limbs were empty. The proximal and defunctionalized limbs showed increased pressure and slower healing despite increased proliferation, ERK protein, and ERK activation. In vitro, pressure decreased Caco-2 migration across collagen or fibronectin, stimulated proliferation, and activated ERK. However, ERK blockade did not prevent pressure effects. CONCLUSIONS: Luminal pressure during obstruction or ileus may impair mucosal healing independently of luminal flow despite increased mitosis and ERK activation.

Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity.

Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.

ERK3 associates with MAP2 and is involved in glucose-induced insulin secretion.

The adaptation of pancreatic islets to pregnancy includes increased beta cell proliferation, expansion of islet mass, and increased insulin synthesis and secretion. Most of these adaptations are induced by prolactin (PRL). We have previously described that in vitro PRL treatment increases ERK3 expression in isolated rat pancreatic islets. This study shows that ERK3 is also upregulated during pregnancy. Islets from pregnant rats treated with antisense oligonucleotide targeted to the PRL receptor displayed a significant reduction in ERK3 expression. Immunohistochemical double-staining showed that ERK3 expression is restricted to pancreatic beta cells. Transfection with antisense oligonucleotide targeted to ERK3 abolished the insulin secretion stimulated by glucose in rat islets and by PMA in RINm5F cells. Therefore, we examined the participation of ERK3 in the activation of a cellular target involved in secretory events, the microtubule associated protein MAP2. PMA induced ERK3 phosphorylation that was companied by an increase in ERK3/MAP2 association and MAP2 phosphorylation. These observations provide evidence that ERK3 is involved in the regulation of stimulus-secretion coupling in pancreatic beta cells.