ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior.

Squamous cell carcinomas (SCCs) arising in the oral cavity are associated with poor survival, mainly due to metastatic disease. In contrast, skin SCCs rarely metastasize and are usually curable. To study influence of tongue and skin stroma on cancer growth and induction of lymphangiogenesis, xenograft tumors of human carcinoma cells were established either in tongue or skin of BALB/c nude mice. Two oral and two skin SCC cell lines were used, as well as an endometrial adenocarcinoma cell line. Tongue tumors established from all cell lines were larger than corresponding skin tumors. Peritumoral lymphatic vessel density was up to five times higher in tongue than in corresponding skin tumors, and mRNA level of the lymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C was twice as high in tongue tumors compared with corresponding skin tumors. Contrary to lymphatic vessel density, blood vessel density was higher in skin tumors than in tongue tumors. In a cohort of patient samples, lymphatic vessel density was found to be higher in tongue SCCs compared with skin SCCs, supporting a clinical relevance of our findings. Our results show that the tumor stroma has a profound impact on cancer growth and induction of lymphangiogenesis and angiogenesis. The difference in lymphatic vessel density between tongue and skin tumors may be important in directing metastatic potential of tumors arising in these organs.

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38 MApK-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38 MApK-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38 MApK-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth. The steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator of the p160 family encoded by the gene nuclear receptor coactivator 3 (NCOA3). It was originally identified as a coactivator for nuclear receptors 1 , but is now recognized as a coactivator of several other transcription factors including E2F transcription factor 1 (E2F1) 2 , polyomavirus enhancer activator 3 (PEA3) 3 , activator protein-1 (AP-1) 4,5 , and nuclear factor-κB (NF-κB) 6,7. Based on this broad spectrum of transcriptional activities, SRC-3 has been shown to play important roles in a wide range of physiological processes, such as cell proliferation, cell survival, mammary gland development 8 and metabolism 9. Since 1997, when SRC-3 was found to be amplified in breast cancer 10 its role in cancer progression has been broadly investigated. It has been shown to be implicated in hormone-related cancers, such as endometrial 11 , ovarian 12 , prostate 13 and breast cancer 14 , but also in in hormone-independent cancer types such as esophageal, squamous cell, colorectal, hepatocellular, pancreatic and non-small cell lung cancer 15. SRC-3 modulates various processes, for example cell proliferation 16 , development of metastasis 17 , and resistances to anti-cancer drugs 18,19. The function of the SRC-3 protein is highly regulated by post-transcriptional modifications through phosphorylation. SRC-3 is phosphorylated at multiple residues mediated by distinct protein kinases, suggesting that SRC-3 might be controlled by several different signaling pathways in health and disease 20,21. Among the different phosphorylation sites, the most frequently reported modification of SRC-3 is the phosphorylation at serine 857 (S857) 22. This phosphorylation has been shown to be important for regulation of estrogen receptor, androgen receptor and NF-κB-mediated transcription 20. In addition, more recent data indicate that phosp...

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Increased expression of the invasion-and metastasisassociated protein S100A4 is found in many types of cancer, but the regulation of S100A4 expression is poorly understood. The microenvironment surrounding tumors has a significant effect on tumor progression, and in the present study, we investigated the role of the microenvironment in the expression of S100A4. Tumors of three different human carcinoma cell lines were established in the tongue or skin of mice, and S100A4 expression was assessed by quantitative RT-PCR, Western blotting, and immunohistochemical analysis in tumors and stromal tissue and in cancer cells grown in vitro. Tongue tumors of the oral squamous cell carcinoma cell line HSC-4 showed a pronounced increase in S100A4 expression during tumor growth, whereas only a minor increase was detected in skin tumors of the same cell line. The S100A4 expression correlated with the methylation status of cytosine-guanine sites in the first intron of the gene. For all cell lines, S100A4 expression in the tumor stroma was related to the presence of inflammatory cells rather than to the level of S100A4 in the tumor cells.

Background Suboptimal medication use contributes to a substantial proportion of hospitalizations and emergency department visits in older adults. We designed a clinical pharmacist intervention to optimize medication therapy in older hospitalized patients. Based on the integrated medicine management (IMM) model, the 5-step IMMENSE intervention comprise medication reconciliation, medication review, reconciled medication list upon discharge, patient counselling, and post discharge communication with primary care. The objective of this study was to evaluate the effects of the intervention on healthcare use and mortality. Methods A non-blinded parallel group randomized controlled trial was conducted in two internal medicine wards at the University Hospital of North Norway. Acutely admitted patients ≥ 70 years were randomized 1:1 to intervention or standard care (control). The primary outcome was the rate of emergency medical visits (readmissions and emergency department visits) 12 months after discharge. Results Of the 1510 patients assessed for eligibility, 662 patients were asked to participate, and 516 were enrolled. After withdrawal of consent and deaths in hospital, the modified intention-to-treat population comprised 480 patients with a mean age of 83.1 years (SD: 6.3); 244 intervention patients and 236 control patients. The number of emergency medical visits in the intervention and control group was 497 and 499, respectively, and no statistically significant difference was observed in rate of the primary outcome between the groups [adjusted incidence rate ratio of 1.02 (95% CI: 0.82–1.27)]. No statistically significant differences between groups were observed for any of the secondary outcomes, neither in subgroups, nor for the per-protocol population. Conclusions We did not observe any statistical significant effects of the IMMENSE intervention on the rate of emergency medical visits or any other secondary outcomes after 12 months in hospitalized older adults included in this study. Trial registration The trial was registered in clinicaltrials.gov on 28/06/2016, before enrolment started (NCT02816086).