Targeting chondroitin sulfate suppresses macropinocytosis of breast cancer cells by modulating syndecan-1 expression.

Accumulation of abnormal chondroitin sulfate (CS) chains in breast cancer tissue is correlated with poor prognosis. However, the biological functions of these CS chains in cancer progression remain largely unknown, impeding the development of targeted treatment focused on CS. Previous studies identified chondroitin polymerizing factor (CHPF; also known as chondroitin sulfate synthase 2) is the critical enzyme regulating CS accumulation in breast cancer tissue. We then assessed the association between CHPF-associated proteoglycans (PGs) and signaling pathways in breast cancer datasets. The regulation between CHPF and syndecan 1 (SDC1) was examined at both the protein and RNA levels. Confocal microscopy and image flow cytometry were employed to quantify macropinocytosis. The effects of the 6-O-sulfated CS-binding peptide (C6S-p) on blocking CS functions were tested in vitro and in vivo. Results indicated that the expression of CHPF and SDC1 was tightly associated within primary breast cancer tissue, and high expression of both genes exacerbated patient prognosis. Transforming growth factor beta (TGF-ß) signaling was implicated in the regulation of CHPF and SDC1 in breast cancer cells. CHPF supported CS-SDC1 stabilization on the cell surface, modulating macropinocytotic activity in breast cancer cells under nutrient-deprived conditions. Furthermore, C6S-p demonstrated the ability to bind CS-SDC1, increase SDC1 degradation, suppress macropinocytosis of breast cancer cells, and inhibit tumor growth in vivo. Although other PGs may also be involved in CHPF-regulated breast cancer malignancy, this study provides the first evidence that a CS synthase participates in the regulation of macropinocytosis in cancer cells by supporting SDC1 expression on cancer cells.

CHST11-modified chondroitin 4-sulfate as a potential therapeutic target for glioblastoma.

Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied in vitro and in vivo. We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent in vitro and in vivo. C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells.

Small intestine submucosa as a growth factor attractor promotes peripheral nerve regeneration by enhancing syndecan-3/glial cell line-derived neurotrophic factor (GDNF) signalling:in vivostudy.

Peripheral nerve regeneration (PNR) following trauma requires the reconstruction of the extracellular matrix (ECM) and the proper stimulation of growth factors. Decellularised small intestine submucosa (SIS) has been extensively used as an ECM scaffold for tissue repair, but its potential to enhance the effects of exogenous growth factors on PNR is not well understood. In this study, we evaluated the effects of SIS implantation combined with glial cell-derived growth factor (GDNF) treatment on PNR in a rat neurorrhaphy model. We found that both SIS and regenerating nerve tissue expressed syndecan-3 (SDC3), one of major heparan sulphate proteoglycans in nerve tissue, and that SDC3 interacted with GDNF in the regenerating nerve tissue. Importantly, the SIS-GDNF combined treatment enhanced the recovery of neuromuscular function andß3-tubulin-positive axonal outgrowth, indicating an increase in the number of functioning motor axons connecting to the muscle after neurorrhaphy. Our findings suggest that the SIS membrane offers a new microenvironment for neural tissue and promotes neural regeneration based on SDC3-GDNF signalling, providing a potential therapeutic approach for PNR.

Targeting Chondroitin Sulphate Synthase 1 (Chsy1) Promotes Axon Growth Following Neurorrhaphy by Suppressing Versican Accumulation.

Versican is a chondroitin sulfate proteoglycan (CSPG), which deposits in perineurium as a physical barrier and prevents the growth of axons out of the fascial boundary. Several studies have indicated that the chondroitin sulfate (CS) chains on versican have several possible functions beyond the physical barrier, including the ability to stabilize versican core protein in the extracellular matrix. As chondroitin sulfate synthase 1 (Chsy1) is a crucial enzyme for CS elongation, we hypothesized that in vivo knockdown of Chsy1 at peripheral nerve lesion site may decrease CS and versican accumulation, and result in accelerating neurite regeneration. In the present study, end-to-side neurorrhaphy (ESN) in Wistar rats was used as an in vivo model of peripheral nerve injury to evaluate nerve regeneration after surgical intervention. The distribution and expression of versican and Chsy1 in regenerating axons after ESN was studied using confocal microscopy and western blotting. Chsy1 was silenced at the nerve lesion (surgical) site using in vivo siRNA transfection. The results indicated that Chsy1 was successfully silenced in nerve tissue, and its downregulation was associated with functional recovery of compound muscle action potential. Silencing of Chsy1 also decreased the accumulation of versican core protein, suggesting that transient treating of Chsy1-siRNA may be an alternative and an effective strategy to promote injured peripheral nerve regeneration.

Effects of the individual three-dimensional printed craniofacial bones with a quick response code on the skull spatial knowledge of undergraduate medical students.

Understanding the three-dimensional (3D) structure of the human skull is imperative for medical courses. However, medical students are overwhelmed by the spatial complexity of the skull. Separated polyvinyl chloride (PVC) bone models have advantages as learning tools, but they are fragile and expensive. This study aimed to reconstruct 3D-printed skull bone models (3D-PSBs) using polylactic acid (PLA) with anatomical characteristics for spatial recognition of the skull. Student responses to 3D-PSB application were investigated through a questionnaire and tests to understand the requirement of these models as a learning tool. The students were randomly divided into 3D-PSB (n = 63) and skull (n = 67) groups to analyze pre- and post-test scores. Their knowledge was improved, with the gain scores of the 3D-PSB group (50.0 ± 3.0) higher than that of the skull group (37.3 ± 5.2). Most students agreed that using 3D-PSBs with quick response codes could improve immediate feedback on teaching (88%; 4.41 ± 0.75), while 85.9% of the students agreed that individual 3D-PSBs clarified the structures hidden within the skull (4.41 ± 0.75). The ball drop test revealed that the mechanical strength of the cement/PLA model was significantly greater than that of the cement or PLA model. The prices of the PVC, cement, and cement/PLA models were 234, 1.9, and 10 times higher than that of the 3D-PSB model, respectively. These findings imply that low-cost 3D-PSB models could revolutionize skull anatomical education by incorporating digital technologies like the QR system into the anatomical teaching repertoire.

Fucosyltransferase 8 modulates receptor tyrosine kinase activation and temozolomide resistance in glioblastoma cells.

Alteration of extracellular glycosylation is a hallmark of malignant characteristics. In this study, we revealed that fucosyltransferase 8 (FUT8), an enzyme that mediates the core fucosylation of N-linked glycosylation, is an important regulator of malignant characteristics in human glioma that acts by modifying the activities of both the HGF receptor (MET) and epidermal growth factor receptor (EGFR). mRNA and protein expression levels of FUT8 were frequently upregulated in gliomas, and these events were showed positive correlations with advanced tumor grade, recurrence, and decreased overall survival. Silencing FUT8 expression in glioma cells suppressed cell growth, migration, and invasion, whereas overexpression of FUT8 was sufficient to enhance these phenotypes. Mechanistic investigations revealed that FUT8 was involved in the alteration of fucosylation status that was attached to MET and EGFR, changing MET responses after HGF stimulation, as well as in the transactivation of EGFR. Importantly, altering FUT8 expression or using the fucosylation inhibitor 2F-peracetyl-fucose sensitized the efficacy of of temozolomide (TMZ) therapy. Collectively, these results suggested that FUT8 dysregulation contributed to the malignant behaviors of glioma cells and provide novel insights into the significance of fucosylation in receptor tyrosine kinase activity and TMZ resistance.

Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin ß1 Expression.

Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin ß1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin ß1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin ß1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma.

CHPF promotes malignancy of breast cancer cells by modifying syndecan-4 and the tumor microenvironment.

Breast cancer is the leading cause of cancer-related deaths in women worldwide. Several studies have indicated that abnormal chondroitin sulfate (CS) chains accumulate in breast cancer tissues; however, the functions and dysregulation of CS synthases are largely unknown. Here, we demonstrate that chondroitin polymerising factor (CHPF) is frequently upregulated in breast cancer tissues and that its high expression is positively associated with tumor metastasis, high stages, and short survival time. CHPF modulates CS formation in breast cancer cells. Additionally, we found that CHPF promotes tumor growth and metastasis accompanied by an increase in G-CSF levels and the number of myeloid-derived suppressor cells in tumor tissue. We revealed that tumor cell-derived G-CSF is co-localised with CS on the cell surface. Interestingly, our study is the first to identify that syndecan-4 (SDC4) is modified by CHPF and that it is involved in CHPF-mediated phenotypes. Moreover, breast cancer patients with high expression of both SDC4 and CHPF had worse overall survival compared to other subsets, which implied the synergistic effects of these two genes. In summary, our results indicated that the upregulation of CHPF in breast cancer contributes to the malignant behaviour of cancer cells, thereby providing novel insights on the significance of CHPF-modified SDC4 in breast cancer pathogenesis.

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-ß Pathways.

Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-ß signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-ß regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME.

Carbonic Anhydrase III Promotes Cell Migration and Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma.

Epithelial-mesenchymal transition (EMT) is strongly correlated with tumor metastasis and contains several protein markers, such as E-cadherin. Carbonic anhydrase III (CA III) exhibits low carbon dioxide hydratase activity in cancer. However, the detailed mechanisms of CA III and their roles in oral cancer are still unknown. This study established a CA III-overexpressed stable clone and observed the expression of CA III protein in human SCC-9 and SAS oral cancer cell lines. The migration and invasion abilities were determined using a Boyden chamber assay. Our results showed that the overexpression of CA III protein significantly increased the migration and invasion abilities in oral cancer cells. Moreover, a whole genome array analysis revealed that CA III regulated epithelial-mesenchymal transition by reducing the expression of epithelial markers. Data from the GEO database also demonstrated that CA III mRNA is negatively correlated with CDH1 mRNA. Mechanistically, CA III increased the cell motility of oral cancer cells through the FAK/Src signaling pathway. In conclusion, this suggests that CA III promotes EMT and cell migration and is potentially related to the FAK/Src signaling pathway in oral cancer.

Corrigendum to "Caffeic Acid Phenethyl Ester Inhibits Oral Cancer Cell Metastasis by Regulating Matrix Metalloproteinase-2 and the Mitogen-Activated Protein Kinase Pathway".

[This corrects the article DOI: 10.1155/2012/732578.].

MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

BACKGROUND: Micro RNAs (miRNAs) are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs) in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a (rs2910164), miRNA149 (rs2292832), miRNA196 (rs11614913), and miRNA499 (rs3746444) genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30). In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80). CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

Impacts of CA9 gene polymorphisms and environmental factors on oral-cancer susceptibility and clinicopathologic characteristics in Taiwan.

BACKGROUND: In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors. METHODOLOGY AND PRINCIPAL FINDINGS: Four single-nucleotide polymorphisms (SNPs) of the CA9 gene from 462 patients with oral cancer and 519 non-cancer controls were analyzed by a real-time polymerase chain reaction (PCR). While the studied SNPs (CA9 rs2071676, rs3829078, rs1048638 and +376 Del) were not associated with susceptibility to oral cancer, the GAA haplotype of 3 CA9 SNPs (rs2071676, rs3829078, and rs1048638) was related to a higher risk of oral cancer. Moreover, the four CA9 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. Finally, patients with oral cancer who had at least one G allele of CA9 rs2071676 were at higher risk for developing lymph-node metastasis (p = 0.022), compared to those patients homozygous for AA. CONCLUSIONS: Our results suggest that the haplotype of rs2071676, rs3829078, and rs1048638 combined has potential predictive significance in oral carcinogenesis. Gene-environment interactions of CA9 polymorphisms, smoking, and betel-quid chewing might alter oral cancer susceptibility and metastasis.

Impacts of microRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer.

BACKGROUND: MicroRNAs (miRNAs) have been regarded as a critical factor in targeting oncogenes or tumor suppressor genes in tumorigenesis. The genetic predisposition of miRNAs-signaling pathways related to the development of oral squamous cell carcinoma (OSCC) remains unresolved. This study examined the associations of polymorphisms with four miRNAs with the susceptibility and clinicopathological characteristics of OSCC. METHODOLOGY/PRINCIPAL FINDINGS: A total of 895 male subjects, including 425 controls and 470 male oral cancer patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a, miRNA196, miRNA499 and miRNA149 genetic polymorphisms between the control group and the case group. This study determined that a significant association of miRNA499 with CC genotype, as compared to the subjects with TT genotype, had a higher risk (AOR = 4.52, 95% CI = 1.24-16.48) of OSCC. Moreover, an impact of those four miRNAs gene polymorphism on the susceptibility of betel nut and tobacco consumption leading to oral cancer was also revealed. We found a protective effect between clinical stage development (AOR = 0.58, 95% CI = 0.36-0.94) and the tumor size growth (AOR = 0.47, 95% CI = 0.28-0.79) in younger patients (age<60). CONCLUSIONS: Our results suggest that genetic polymorphism of miRNA499 is associated with oral carcinogenesis, and the interaction of the miRNAs genetic polymorphism and environmental carcinogens is also related to an increased risk of oral cancer in Taiwanese.

Smoking, green tea consumption, genetic polymorphisms in the insulin-like growth factors and lung cancer risk.

Insulin-like growth factors (IGFs) are mediators of growth hormones; they have an influence on cell proliferation and differentiation. In addition, IGF-binding protein (IGFBP)-3 could suppress the mitogenic action of IGFs. Interestingly, tea polyphenols could substantially reduce IGF1 and increase IGFBP3. In this study, we evaluated the effects of smoking, green tea consumption, as well as IGF1, IGF2, and IGFBP3 polymorphisms, on lung cancer risk. Questionnaires were administered to obtain the subjects' characteristics, including smoking habits and green tea consumption from 170 primary lung cancer cases and 340 healthy controls. Genotypes for IGF1, IGF2, and IGFBP3 were identified by polymerase chain reaction. Lung cancer cases had a higher proportion of smoking, green tea consumption of less than one cup per day, exposure to cooking fumes, and family history of lung cancer than controls. After adjusting the confounding effect, an elevated risk was observed in smokers who never drank green tea, as compared to smokers who drank green tea more than one cup per day (odds ratio (OR) = 13.16, 95% confidence interval (CI) = 2.96-58.51). Interaction between smoking and green tea consumption on lung cancer risk was also observed. Among green tea drinkers who drank more than one cup per day, IGF1 (CA)(19)/(CA)(19) and (CA)(19)/X genotypes carriers had a significantly reduced risk of lung cancer (OR = 0.06, 95% CI = 0.01-0.44) compared with IGF1 X/X carriers. Smoking-induced pulmonary carcinogenesis could be modulated by green tea consumption and their growth factor environment.

Caffeic Acid phenethyl ester inhibits oral cancer cell metastasis by regulating matrix metalloproteinase-2 and the mitogen-activated protein kinase pathway.

Caffeic acid phenethyl ester (CAPE), an active component extracted from honeybee hives, exhibits anti-inflammatory and anticancer activities. However, the molecular mechanism by which CAPE affects oral cancer cell metastasis has yet to be elucidated. In this study, we investigated the potential mechanisms underlying the effects of CAPE on the invasive ability of SCC-9 oral cancer cells. Results showed that CAPE attenuated SCC-9 cell migration and invasion at noncytotoxic concentrations (0 µM to 40 µM). Western blot and gelatin zymography analysis findings further indicated that CAPE downregulated matrix metalloproteinase-2 (MMP-2) protein expression and inhibited its enzymatic activity. CAPE exerted its inhibitory effects on MMP-2 expression and activity by upregulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and potently decreased migration by reducing focal adhesion kinase (FAK) phosphorylation and the activation of its downstream signaling molecules p38/MAPK and JNK. These data indicate that CAPE could potentially be used as a chemoagent to prevent oral cancer metastasis.

Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. The insulin-like growth factors (IGFs) system consists of a group of proteins which may induce cell proliferation and inhibit cell apoptosis through several signal pathways, leading to transformation of normal cells into cancer cells. However, the impact of genetic polymorphisms of the IGFs system on HCC has not been clarified. METHODS: In this case-control study, a total of 102 HCC patients and 306 age- and gender-matched controls were recruited. The genetic polymorphisms of the IGFs system genes, including IGF-1, IGF-2, IGF-1receptor (IGF-1R), IGF-2R, IGF binding protein (IGFBP-3), and insulin (INS) genes, were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and real-time PCR genotyping analysis. RESULTS: A significant difference (p = 0.02) between case and control group in the distribution frequency of IGF-2 +3580 polymorphism was observed. Multiple regression model analysis showed that the presence of AA or AG at IGF-2R may exhibit a potential protective effect against hepatitis C [odds ratio (OR) = 0.35, 95% confidence interval (CI) = 0.15-0.82]. The combination of IGF-2 +3580 AA genotype and IGF-2R GG genotype may present a significantly lower risk of HCC (OR = 0.20, 95% CI = 0.05-0.87). Additionally, no polymorphisms of any IGFs system genes were associated with liver-related clinicopathological markers in serum. CONCLUSIONS: Among IGFs system genes, IGF-2 and IGF-2R gene polymorphisms and combination could be considered as the most important factors contributing to increased susceptibility and pathological development of HCC.

Stromal cell-derived factor-1 but not its receptor, CXCR4, gene variants increase susceptibility and pathological development of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide. Genetic polymorphism has been reported as a predictive factor related to a higher risk for HCC. Because the stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have been reported to play important roles in tumor cell proliferation, angiogenesis, and metastasis of HCC, the aim of this study was to estimate the relationship between SDF-1 and CXCR4 gene variants to HCC risk and clinicopathological status. METHODS: Polymerase chain reaction-restriction fragment length polymorphism was used to measure SDF-1 (rs1801157) and CXCR4 (rs2228014) gene polymorphisms in 311 healthy controls and 102 patients with HCC. RESULTS: Compared to controls, individuals with at least one A allele had a higher risk of 1.57-fold (95% CI: 1.00-2.47) to induce HCC and had a risk of 2.81-fold (95% CI: 1.04-7.58) to develop a status of stage III or stage IV disease, after being adjusted for other confounders. However, there was no significant association between CXCR4 gene polymorphism and either HCC risk or pathological status. Additionally, both gene polymorphisms were not associated with the serum expression of liver-related clinical pathological markers. CONCLUSIONS: SDF-1-3'A gene polymorphism could be considered as a factor related to an increased susceptibility to the risk and pathological development of HCC.