Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

Abstract Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease-specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial-mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4-hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression.Peer reviewe

Allergiat ja niiden ehkäiseminen kasvihuonetyössä : loppuraportti tutkimuksesta biologinen torjunta kasvihuoneissa – altistuminen, allergiat ja niiden ehkäisy

Suomessa toimii ympärivuotisesti noin 60 tomaatti- ja kurkkukasvihuoneyritystä. Kasvihuonetuholaisten torjuntaan käytetään pääsääntöisesti biologisia torjuntaeliöitä, joiden avulla on voitu korvata monia haitallisia torjuntakemikaaleja. Kuitenkin ne, kuten muutkin kasvihuoneissa esiintyvät pieneliöt ja tuotantokasvit, voivat aiheuttaa työntekijöille allergiaa. Tämän tutkimuksen päätavoitteena oli selvittää allergioiden esiintyvyyttä kasvihuonetyöntekijöillä sekä vähentää allergisia ammattitauteja kehittämällä turvallisia työtapoja ja lisäämällä alan tietämystä allergioista. Hankkeen pohjalta laadittiin ohjeet työpaikoille ja työterveyshuoltoon allergioiden ehkäisemiseksi ja allergiaa aiheuttavien tekijöiden arviointiin. Lisäksi tuotettiin turvallisiin työtapoihin ohjaava animaatio, joka soveltuu työntekijöille kielitaidosta riippumatta. Tässä raportissa esitetään tutkimuksen ”Biologinen torjunta kasvihuoneissa – altistuminen, allergiat ja niiden ehkäisy” päätulokset ja johtopäätökset

Metastatic Outgrowth Encompasses COL-I, FN1, and POSTN Up-Regulation and Assembly to Fibrillar Networks Regulating Cell Adhesion, Migration, and Growth

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-β signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes—all inducible by transforming growth factor-β. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-β receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis