Disease relevance of SPARCL1

• Originally we identified SPARCL1 as one of the genes down regulated in human non-small cell lung cancer (NSCLC) [1].
• Recent reports indicate that the down regulation of SPARCL1 also occurs in prostate and colon carcinomas, suggesting that SPARCL1 inactivation is a common event not only in NSCLCs but also in other tumors of epithelial origin [1].
• Using Northern and Western blot analysis, we showed that MAST9 was down-regulated in the tumor samples of nine non-small cell lung carcinoma patients [2].
• In the extracellular matrix of cultured osteosarcoma cells SC1 was found associated with collagen I-containing fibrils, and binding of SC1 to reconstituted collagen I fibrils could be demonstrated by immunogold labeling and electron microscopy [3].
• In this Prospect article we summarize evidence for SPARC and hevin in the regulation of tumor cell growth, differentiation, and metastasis, and we propose that matricellular proteins such as these perform critical functions in desmoplastic responses of tumors that culminate in their dissemination and eventual colonization of other sites [4].

High impact information on SPARCL1

• Hevin could contribute to the induction or maintenance of features of the HEV endothelium that facilitate lymphocyte migration [5].
• Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin: parallels to CD34 [6].
• Adhesion molecules of cultured hematopoietic malignancies. A calcium-dependent lectin is the principle mediator of binding to the high endothelial venule of lymph nodes [7].
• The lymphocyte-high endothelial venule (HEV) cell interaction is an essential element of the immune system, as it controls lymphocyte recirculation between blood and lymphoid organs in the body [8].
• Long-term SC1-expanded murine ES cells can be differentiated into cells of the three primary germ layers in vitro and also can generate chimeric mice and contribute to the germ line in vivo [9].

Biological context of SPARCL1

• We also sequenced the 5'-flanking region of the human SPARCL1 gene containing 2.4 kb of the putative promoter region [1].
• Using fluorescence in situ hybridization analysis, SPARCL1 was localized to chromosome 4q22-25, a region often deleted in human cancers [1].
• SPARCL1 contains 11 exons and 10 introns which span approximately 47 kb of the genome [1].
• Hevin is expressed during embryogenesis and tissue remodeling and is especially prominent in brain and vasculature [10].
• Therefore, SPARCL1 was suggested to be a tumor suppressor gene [11].

Anatomical context of SPARCL1

• Modulation of endothelial cell adhesion by hevin, an acidic protein associated with high endothelial venules [12].
• Here, we show that this protein, designated hevin, is associated with basal, lateral, and apical surfaces of HEV cells, and unlike MECA-79 antigen, is not expressed on the underlying basement membrane [12].
• Hevin-treated cells do not form focal adhesions and exhibit a rounded morphology [12].
• Although SC1/ECM2 is normally a secreted protein, we show that it is also capable of augmenting lymphopoiesis when expressed as a transmembrane protein on fibroblasts [13].
• A fusion protein prepared from the full length of SC1/ECM2 and Ig was found to recognize pre-B cells in a divalent cation-dependent manner, and to augment mitogen-dependent proliferation of mature B cells, as well as the cloning of pre-B cells, but to have no influence on myeloid progenitor cells [13].

Associations of SPARCL1 with chemical compounds

• As an initial step towards investigating the functional role of Hevin in cell growth and differentiation, we transiently or stably expressed this gene in cancer cells (HeLa 3S) that are devoid of endogenous Hevin and measured DNA synthesis (cell proliferation) by 5-bromo-2'-deoxyuridine incorporation [14].
• Matrix glycoprotein SC1/ECM2 (SC1/ECM2), a calcum-binding secreted protein, is one example and can contribute to the nurturing environment for B lymphocyte precursors [15].
• In this work, we show that removal of chondroitin sulfate by chondroitinase treatment of lymphocytes or incubation of HEV with chondroitin sulfate does not significantly inhibit lymphocyte binding to HEV, suggesting that chondroitin sulfate is not involved in endothelial cell recognition of lymphocytes [8].
• Lymphocytes express integrin receptors, termed lymphocyte Peyer's patch high endothelial venule (HEV) adhesion molecules (LPAMs), that mediate their organ-specific adhesion to specialized HEVs found in mucosal lymphoid organs (Peyer's patches) [16].
• Using gene expression profiling of mucosal addressin cell adhesion molecule-1(+) mesenteric lymph node HEV cells by quantitative 3'-cDNA collection, we have identified a leucine-rich protein, named leucine-rich HEV glycoprotein (LRHG) that is selectively expressed in these cells [17].

Regulatory relationships of SPARCL1

• Moreover, addition of soluble exogenous hevin inhibits attachment and spreading of endothelial cells on fibronectin substrates [12].
• Furthermore, we have shown that Hevin can inhibit progression of cells from G1 to S phase or prolong G1 phase [14].
• Immunohistochemical analyses indicated that SHPS-1 is expressed on high endothelial venule as well as macrophages in human tonsils [18].

Other interactions of SPARCL1

• Its down-regulation in a number of cancers and the possibility of its functional compensation by SPARC has led to recent interest in hevin as a tumor suppressor and regulator of angiogenesis [10].
• Interaction of myocilin with the C-terminal region of hevin [19].
• A fusion protein prepared from the amino terminal portion of SC1/ECM2 and the constant region of human Ig preferentially bound to pre-B cells [13].
• We present evidence for an altered collagen matrix and levels of the proteoglycan decorin in the normal dermis and dermal wound bed of hevin-null mice [20].
• We have cloned a human Hevin cDNA from omental adipose tissue of different patients by reverse transcription polymerase chain reaction and shown a sequence variation due to a possible polymorphism at amino acid position 161 (E/G) [14].

Analytical, diagnostic and therapeutic context of SPARCL1

• By microsatellite analysis, real-time quantitative PCR, and sequence analysis of all exons including the intron-exon junctions and a part of the putative promoter region, we could not find any deletion or mutation that might be responsible for the downregulation of SPARCL1 in NSCLC [11].
• In electron microscopy, after negative staining, SC1 was revealed as a globule attached to a thread-like structure [3].
• Using Northern blots and a human expressed sequence tAg database analysis, Hevin was shown to be widely expressed in human normal or non-neoplastic diseased tissues with various levels [14].
• Overexpression of Hevin in tumour xenografts also significantly delayed tumour growth [21].
• SPARC and Hevin protein and mRNA expression in HCC specimens were assessed by immunostaining, immunoblotting, and quantitative reverse transcriptase-polymerase chain reaction [21].

References