The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells

Baldi, Alfonso; Luca, Antonio De; Morini, Monica; Battista, Tullio; Felsani, Armando; Baldi, Feliciano; Catricalà, Caterina; Amantea, A.; Noonan, Douglas M.; Albini, Adriana; Natali, Pier Giorgio; Lombardi, Doug; Paggi, Marco G.

doi:10.1038/sj.onc.1205911

Cited by 186 publications

(196 citation statements)

References 29 publications

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“…22 Other groups have used microarrays to analyze the gene expression profile of melanoma vs dysplastic nevi 23 or to determine which genes are operative in the transformation from localized to metastatic melanoma. [24][25][26][27][28] As expected, the progression from radial to vertical growth phase is associated with loss of cell cycle regulatory control. For example, cyclin D1 is expressed in radial growth phase melanoma and is lost in progression to vertical growth phase neoplasms, while p16 (INK4A) and p27 (KIP1) expression are diminished in advanced melanoma.…”

Section: Molecular Adjuncts To Diagnosis: the Microarraysupporting

confidence: 55%

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The future of dermatopathology

Crowson

2006

Modern Pathology

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Of the major issues that dermatopathology will face in the immediate future, two powerful challenges loom large. The first is the application of novel nondestructive imaging technologies to in vivo diagnosis in humans. The second is the application of molecular technologies to a diagnostic arena which formerly belonged exclusively to the light microscopist. The first to be considered in this context is the application of near infrared spectroscopy to the noninvasive in vivo diagnosis of neoplastic skin disease. The second will be a discussion of application, methodology and the current state of the art in microarray technologies as they apply to neoplastic dermatopathology and, in particular, the diagnosis and prognostication of melanoma. Modern Pathology (2006) 19, S155-S163. doi:10.1038/modpathol.3800513Keywords: in vivo microscope; tissue microarray; basal cell carcinoma; infrared spectroscopy Noninvasive assessment of skin lesions by near infrared (IR) spectroscopyIn the late 1990s, working with Dr Laura McIntosh and colleagues at the National Research Council of Canada, the University of Manitoba, Central Medical Laboratories and the Misericordia General Hospital in Winnipeg, Canada, we designed and patented a noninvasive tool for the diagnosis of skin tumors using visible and near IR spectroscopy in the 400-2500 nm size wavelength range. 1-5 Initially, we excised neoplasms, and processed them in the fresh state with sections for formaldehyde fixation and paraffin embedding matched to tissue elements snap frozen in liquid nitrogen and stored at À801F. Thick sections from the frozen tissue elements were interrogated by mid-IR wavelength light (Figure 1). The transmitted light generated significant spectral differences; water, hemoglobin, cytochromes, lipids and proteins all absorb light at specific frequencies ( Figure 2). In particular, the mid-IR range is rich with information about proteins including in the context of collagen and RNA. When analyzed by a sophisticated leave-one-out hierarchical classification algorithm, distinction between microanatomic compartments of the skin could be made (Figure 3). Using this methodology, we were able with an accuracy of 90-95% to distinguish basal cell carcinoma (BCC) from melanocytic nevi, seborrheic keratoses and squamous cell carcinomata in vitro. Melanocytic nevi could be subdivided into banal vs dysplastic nevi based upon their spectral differences and melanomas could be separately recognized as well. Furthermore, the different types of lesion were shown to have distinct mid-IR signatures when compared to adjacent normal epidermal and dermal compartments.Unfortunately, the diagnostic potential of mid-IR spectroscopy for in vivo applications is limited, as complete absorption of mid-IR light occurs with samples greater than 10-15 mm in thickness. In contrast, near-IR light scatters to a much greater extent than it absorbs and in consequence, tissues are relatively transparent in the near-IR region which permits the examination of larger tissue volumes and led to...

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Section: Molecular Adjuncts To Diagnosis: the Microarraysupporting

confidence: 55%

“…31 In addition to WNT5A, other genes are implicated in the acquisition of cell motility and angiogenesis. 25,26,[32][33][34] Hypoxia-inducible genes such as Cyr61 have shown to be constitutively upregulated in late stage melanoma. 35 Complementary to cDNA microarray is the tissue microarray.…”

Section: Molecular Adjuncts To Diagnosis: the Microarraymentioning

confidence: 99%

The future of dermatopathology

Crowson

2006

Modern Pathology

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“…The expression of HtrA1 and HtrA3 is decreased in several cancers, while overexpression of HtrA1 in human cancers inhibits cell growth and proliferation (91)(92)(93)(94). These results suggest a tumor suppressor function for HtrA proteinases.…”

Section: High-temperature Requirement Proteinasesmentioning

confidence: 88%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…HTRA2 is the best characterized of the four and exists as a membrane protein primarily involved in mitochondrial quality control [2,3]. Both HTRA1 and HTRA2 are primarily regarded as being key regulators of tumor development and subsequent malignancies [4][5][6], although a growing body of evidence now exists to suggest that HTRA1 may also play a central role in musculoskeletal development and disease through its proteolytic actions on proteins within the extracellular matrix (ECM) [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

et al. 2012

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Mammalian high-temperature requirement serine protease A1 (HTRA1) is a secreted member of the trypsin family of serine proteases which can degrade a variety of bone matrix proteins and as such has been implicated in musculoskeletal development. In this study, we have investigated the role of HTRA1 in mesenchymal stem cell (MSC) osteogenesis and suggest a potential mechanism through which it controls matrix mineralization by differentiating boneforming cells. Osteogenic induction resulted in a significant elevation in the expression and secretion of HTRA1 in MSCs isolated from human bone marrow-derived MSCs (hBMSCs), mouse adipose-derived stromal cells (mASCs), and mouse embryonic stem cells. Recombinant HTRA1 enhanced the osteogenesis of hBMSCs as evidenced by significant changes in several osteogenic markers including integrin-binding sialoprotein (IBSP), bone morphogenetic protein 5 (BMP5), and sclerostin, and promoted matrix mineralization in differentiating boneforming osteoblasts. These stimulatory effects were not observed with proteolytically inactive HTRA1 and were abolished by small interfering RNA against HTRA1. Moreover, loss of HTRA1 function resulted in enhanced adipogenesis of hBMSCs. HTRA1 Immunofluorescence studies showed colocalization of HTRA1 with IBSP protein in osteogenic mASC spheroid cultures and was confirmed as being a newly identified HTRA1 substrate in cell cultures and in proteolytic enzyme assays. A role for HTRA1 in bone regeneration in vivo was also alluded to in bone fracture repair studies where HTRA1 was found localized predominantly to areas of new bone formation in association with IBSP. These data therefore implicate HTRA1 as having a central role in osteogenesis through modification of proteins within the extracellular matrix. STEM CELLS

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The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells

Cited by 186 publications

References 29 publications

The future of dermatopathology

The future of dermatopathology

Emerging roles of serine proteinases in tissue turnover in arthritis

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

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