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since selenium ( se ) is an essential trace element for humans and animals and its deficiency has been found prevalent in certain geographical areas , its supplementation is required to prevent various types of diseases , such as man sterility , cancer , and neurodegenerative diseases .
selenium exerts its biochemical and metabolic effects through selenoproteins , which include glutathione peroxidases , thioredoxin reductases , and iodothyronine deiodinases and are characterized by the selenium co - translational incorporation as selenocysteine , the 21 amino acid , at uga codons , which typically serve as stop codons . in particular , 25 selenoproteins have been found in humans and 24 in rodents .
most of them play important roles in redox regulation , detoxification , immune - system protection and viral suppression , whereas the biological functions of some newly identified selenoproteins remain unknown .
selenoprotein m ( selm ) is a recently discovered endoplasmic reticulum ( er)-resident selenoprotein , highly expressed in the brain .
structural studies have revealed that this protein possesses a selenocysteine containing cxxu ( u = selenocysteine ) thioredoxin - like domain and suggested that it acts as a thioldisulfide oxidoreductase participating in disulfide bond formation . in particular , selm is 145 amino acids long with the central / domain composed of a two - layer / sandwich with a mixed four - stranded -sheet and an -helices pair packed on -sheet side .
previous works demonstrated that over - expression of human selm in the cmv / gfp - hselm rats increased the antioxidant enzymes activity such as glutathione peroxidase ( gpx ) and superoxide dismutase ( sod ) .
in fact , selm knock - down raises the calcium baseline in the cells while selm knock - down exhibits blebbing that may be indicative of apoptosis .
furthermore , selm knock - down decreases the cell viability and increases the reactive oxygen species ( ros ) production , further demonstrating the functional importance of selm in preventing oxidative stress .
a report also showed that the activation of mitogen - activated protein kinase ( mapk ) pathway , induced by selenium treatment , significantly down - regulates /-secretase activity and tau phosphorylation in the transgenic rat over - expressing human selm . since the three members in the mammalian mapk family are the extracellular signal - regulated kinase ( erk ) , the c - jun nh2-terminal kinase ( jnk ) , and p38 , and that erk signaling pathway is involved in promoting cell proliferation , migration , and survival , their association with hepatocellular carcinoma ( hcc ) progression can play important roles during hcc development .
therefore , all these data suggested a possible correlation among selm , selenoproteins and hcc .
recently , our group has evaluated the selm expression in two human hepatocellular carcinoma cell lines , hepg2 and huh7 , compared to normal hepatocytes , and evidenced its over - expression in both the cell lines .
this led us to investigate also its expression in human hcc tissue samples , opening to its putative use as reasonable cancer marker .
hence , in this article we have evaluated by immunohistochemistry ( ihc ) the selm expression in tissue samples from hcc patients and verified its over - expression .
paraffin - embedded hcc tissues obtained by biopsy from thirty patients were subjected to ihc .
all patients in this study provided informed consent , and the study was approved by the second university of naples ethics committee .
, all patients had hcv - related cirrhosis and included ten hcc with grade i , eleven hcc with grade ii , and nine hcc with grade iii .
briefly , xylene dewaxed and alcohol rehydrated paraffin sections were placed in coplin jars filled with a 0.01 m tri - sodium citrate solution and microwaved .
sections were immersed in 3% h2o2 at room temperature for 30 min to block any endogenous peroxidase activity .
they were then washed in tris - buffered saline ( tbs ) ph 7.4 before incubating at 4c overnight with rabbit monoclonal anti - human selm ( lifespan biosciences inc . ,
after incubation with the primary antibody , tissue sections were stained with species - specific biotinylated secondary antibodies , followed by peroxidase labeled streptavidine ( dako , glostrup , denmark ) ; the signal was developed by using diaminobenzidine ( dab ) chromogen ( dako ) as substrate .
associations between immunohistochemical scores and clinicopathological characteristics of tissue specimens were evaluated by pearson correlation coefficients and p<0.05 was considered statistically significant .
were utilized in the evaluation of immunoreactivity for both staining intensity and percentage positive of stained tumor cells .
the percentage of positive cells that revealed stronger staining intensity in respect to the adjacent hepatocyte cells were scored as follows : 0 ( if 0 - 4% of tumor cells were stained ) , 1 ( if 5 - 25% of tumor cells were stained ) , 2 ( if 26 - 50% of tumor cells were stained ) , 3 ( if 51 - 75% of tumor cells were stained ) and 4 ( if more than 75% of tumor cells were stained ) . in order to determine the staining intensity , these categories were subclassified as follows : 0 : no expression , 1 : extremely weak , 2 : weak , 3 : moderate and 4 : strong expression .
paraffin - embedded hcc tissues obtained by biopsy from thirty patients were subjected to ihc .
all patients in this study provided informed consent , and the study was approved by the second university of naples ethics committee .
, all patients had hcv - related cirrhosis and included ten hcc with grade i , eleven hcc with grade ii , and nine hcc with grade iii .
briefly , xylene dewaxed and alcohol rehydrated paraffin sections were placed in coplin jars filled with a 0.01 m tri - sodium citrate solution and microwaved . after heating
sections were immersed in 3% h2o2 at room temperature for 30 min to block any endogenous peroxidase activity .
they were then washed in tris - buffered saline ( tbs ) ph 7.4 before incubating at 4c overnight with rabbit monoclonal anti - human selm ( lifespan biosciences inc . ,
after incubation with the primary antibody , tissue sections were stained with species - specific biotinylated secondary antibodies , followed by peroxidase labeled streptavidine ( dako , glostrup , denmark ) ; the signal was developed by using diaminobenzidine ( dab ) chromogen ( dako ) as substrate .
associations between immunohistochemical scores and clinicopathological characteristics of tissue specimens were evaluated by pearson correlation coefficients and p<0.05 was considered statistically significant .
were utilized in the evaluation of immunoreactivity for both staining intensity and percentage positive of stained tumor cells .
the percentage of positive cells that revealed stronger staining intensity in respect to the adjacent hepatocyte cells were scored as follows : 0 ( if 0 - 4% of tumor cells were stained ) , 1 ( if 5 - 25% of tumor cells were stained ) , 2 ( if 26 - 50% of tumor cells were stained ) , 3 ( if 51 - 75% of tumor cells were stained ) and 4 ( if more than 75% of tumor cells were stained ) . in order to determine the staining intensity , these categories were subclassified as follows : 0 : no expression , 1 : extremely weak , 2 : weak , 3 : moderate and 4 : strong expression .
collected tissues were subjected to selm staining by ihc that is highly specific , because it detects a positivity only in the hepatocytes cytoplasm with exclusion of sinusoidal endothelial cells , kuppfer cells or mesenchymal cells resulting by sclerotic - phlogistic processes ( figure 1 a , b ) . as shown in figure 2 ,
selm expression resulted positive in all the stained hcc tissues whereas in the corresponding cirrhotic tissues ( used as control ) we observed a light and discontinuous positivity ( figure 2 a , e ) , that is especially noticeable at the level of foci in proliferating hepatocytes mainly in those cells with medium or high grade of dysplasia ( figure 2e ) .
observations at 20x and 40x magnifications showed that : i ) in hcc grade i selm stain is clean and marked in the cytoplasm of hepatocytes carcinomatosis in areas of proliferative activity and at the level of tumor growth poles ( figure 2 b , f ) ; ii ) in hcc grade ii selm stain is much extended , with a net positivity for this antigen in the majority of the cellular population both at the level of tumor growth poles and in areas of greater cellular undifferentiation ( figure 2 c , g ) ; and iii ) in hcc grade iii selm stain is explicitly very strong and widespread in hepatocytes and through this widespread immunopositivity is possible to detect a greater stain grade in binuclear and high undifferentiation hepatocytes ( figure 2 d , h ) .
these evaluations have suggested that the gradual raise of selm expression was associated with an increased malignant grade ( figure 3 ) .
actually , the cells percentage and the expression intensity increased from better differentiated histopathological forms to those poorly differentiated .
in particular , using scoring methods proposed by sinicrope et al . we can underline that : i ) seven hcc tissue samples displayed a weak expression ( with score=2 ) ; ii ) thirteen revealed a moderate expression ( with score=3 ) ; and iii ) ten evidenced a strong expression ( with score=4 ) ( figure 3 ) .
we have also evaluated the correlation coefficients between selm expression and clinicpathological features ( table 1 ) .
a significant correlation was detected between the immunohistochemical histochemical scores and grading ( p<0.0001 and r=0.86 ) whereas no correlation was obtained between selm expression and age / gender/ tumor size .
selenium beneficial influence is attributed to its presence within selenoproteins , a group of proteins containing the rare selenocysteine amino acid .
this family of proteins includes glutathione peroxidases , thioredoxin reductases , iodothyronine deiodinases and other selenoproteins such as selm , which is located in the endoplasmic reticulum .
deficiency in selenium is associated with a range of morbidities , such as immunosuppression , viral infections , hypothyroidism , cardiovascular diseases and cancers .
recently , the downregulation of gpx3 was associated with lymph node metastasis and prognosis in cervical cancer , whereas the lower levels of sepp1 with an increasing risk of lung cancer among blacks but not whites . moreover ,
sepp1 gene was statistically significantly associated with breast cancer risk among women with higher native american ancestry and gpx1 , gpx3 , and sels with estrogen receptor-/progesterone receptor+ status .
lower sepp1 concentrations resulted to correlate also with higher tumor grade and tumor stage in patients with renal cancer .
however , data from case - control studies suggested that a variant in gpx1 influenced the effect of se status on prostate , breast and lung cancer risk , whereas variants in gpx4 , sepp1 and sels may influence the risk of colorectal cancer . on the other hand
in fact , carlson et al . showed in mice with specific excision of the selenocysteine trna the plasma sepp1 levels were reduced by about 75% , suggesting that it was primarily exported from the liver . in fact , most of this animals died after 1 and 3 months of age due to severe hepatocellular degeneration and necrosis with concomitant necrosis of peritoneal and retroperitoneal fat .
moreover , it was evaluated the expression of some selenoproteins in a well - characterized transgenic mouse model of liver cancer , in which hepatocyte - specific coexpression of c - myc oncogene and transforming growth factor alpha ( tgf ) leads to rapid hcc development with high penetrance . in details , in the tumors derived from 6-month - old mice , the expression of gpx1 was significantly reduced , whereas expression of tr1 appeared to be slightly elevated suggesting the possibility that tumorigenesis alters selenoprotein expression in these mice . moreover , in our recent papers we have carried out the differences of selm expression between normal hepatocytes and two human hcc cell lines , hepg2 and huh7 and , then , have performed a global analysis of the selenotranscriptome expression in hepg2 and huh7 cells compared to the normal human hepatocytes showing that in both cells there are some down - regulated and up - regulated genes .
therefore , we evaluated the selm expression in tissue samples from patients with hcc by ihc and verified its over - expression in excellent agreement with our previous paper . in general , this report evidences for the first time that the selm over - expression in hcc tissues can be easily and precisely detected by the simple immunohistochemistry technique .
therefore , we can suggest that the evaluation of selm expression in hcc patients liver tissues could be a good prognostic tool for understanding hcc progression .
however , further researches are needed to study selm biological function in hcc development and progression .
selenium is an essential trace mineral of fundamental importance to human healthy and exerts its biological function through selenoproteins . in particular , selenoprotein m ( selm ) 
 is located in the endoplasmic reticulum and contains the common redox motif of cysteine - x - x - selenocysteine type . 
 it attracts great attention due to its high expression in brain and its potential roles as antioxidant , neuroprotective , and cytosolic calcium regulator . 
 recently , our group found selm over - expression in human hepatocellular carcinoma ( hcc ) cell lines . in this report some paraffin - embedded tissues from liver biopsy of patients with hepatitis c virus ( hcv)-related cirrhosis and hcc were immunohistochemically stained and selm expression scoring was evaluated . 
 our results evidence for the first time an increase of selm expression in hcc liver tissues , and its gradual expression raise associated with an increased malignancy grade . 
 therefore , we propose to use i ) selm as putative marker for hcc as well as ii ) simple immunohistochemistry technique to distinguish between the different grades of malignancy .