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CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.

Neve Polimeno M, Ierano C, D'Alterio C, Simona Losito N, Napolitano M, Portella L, Scognamiglio G, Tatangelo F, Maria Trotta A, Curley S, Costantini S, Liuzzi R, Izzo F, Scala S - Cell. Mol. Immunol. (2014)

Bottom Line: When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03).Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032).In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not.

View Article: PubMed Central - PubMed

Affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.

ABSTRACT
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

No MeSH data available.


Related in: MedlinePlus

CXCR4, CXCR7 and CXCL12 mRNA expression in HCC. (a) Quantitative reverse transcriptase PCR analysis for CXCR4, CXCR7 and CXCL12 levels in HCC patients. mRNA expression was measured using real-time PCR in normal liver (NL) and HCC. The y-axis values represent the ratio between the value of each gene in HCC/normal liver normalized to GUSB RNA expression. Each assay was performed in triplicate. (b) Relative box plot. (c) Immunohistochemical CXCL12 evaluation. Upper left: peritumoral liver tissue; upper right: HCC tissue (magnification: ×5). Lower left: detail peritumoral liver tissue; lower right: detail HCC tissue (magnification: ×40). HCC, hepatocellular carcinoma; PCR, polymerase chain reaction.
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fig3: CXCR4, CXCR7 and CXCL12 mRNA expression in HCC. (a) Quantitative reverse transcriptase PCR analysis for CXCR4, CXCR7 and CXCL12 levels in HCC patients. mRNA expression was measured using real-time PCR in normal liver (NL) and HCC. The y-axis values represent the ratio between the value of each gene in HCC/normal liver normalized to GUSB RNA expression. Each assay was performed in triplicate. (b) Relative box plot. (c) Immunohistochemical CXCL12 evaluation. Upper left: peritumoral liver tissue; upper right: HCC tissue (magnification: ×5). Lower left: detail peritumoral liver tissue; lower right: detail HCC tissue (magnification: ×40). HCC, hepatocellular carcinoma; PCR, polymerase chain reaction.

Mentions: To evaluate if the chemokine receptor levels are due to increased transcription, the mRNA levels of CXCR4, CXCR7 and CXCL12 were evaluated in 33/86 frozen tissues using real-time PCR (Figure 3a). CXCR4 mRNA was upregulated in 15/33 (45.5%) HCC patients, and CXCR7 expression was increased in 18/33 (54.5%) patients. In 23/33 (69.7%) HCC patients, CXCR7 was overexpressed compared to CXCR4 (mean fold change 5.5), whereas in 9/33 samples (27.3%), CXCR4 was upregulated (mean fold change 4.4) compared to CXCR7 levels. Interestingly, the ligand CXCL12 was overexpressed in the tumor tissue in only three cases, although in 30/33 (90.9%) cases, CXCL12 was overexpressed in peritumoral tissue (mean fold change: 13.5). In Figure 3b, the relative box-plot demonstrates that CXCL12 expression was significantly different between tumor and peritumoral tissues, with lower expression in tumor tissues (P=0.032). CXCL12 was also evaluated using immunohistochemistry, which confirmed a lower expression level in the tumor tissues compared to peritumoral tissues (Figure 3c).


CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.

Neve Polimeno M, Ierano C, D'Alterio C, Simona Losito N, Napolitano M, Portella L, Scognamiglio G, Tatangelo F, Maria Trotta A, Curley S, Costantini S, Liuzzi R, Izzo F, Scala S - Cell. Mol. Immunol. (2014)

CXCR4, CXCR7 and CXCL12 mRNA expression in HCC. (a) Quantitative reverse transcriptase PCR analysis for CXCR4, CXCR7 and CXCL12 levels in HCC patients. mRNA expression was measured using real-time PCR in normal liver (NL) and HCC. The y-axis values represent the ratio between the value of each gene in HCC/normal liver normalized to GUSB RNA expression. Each assay was performed in triplicate. (b) Relative box plot. (c) Immunohistochemical CXCL12 evaluation. Upper left: peritumoral liver tissue; upper right: HCC tissue (magnification: ×5). Lower left: detail peritumoral liver tissue; lower right: detail HCC tissue (magnification: ×40). HCC, hepatocellular carcinoma; PCR, polymerase chain reaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4496532&req=5

fig3: CXCR4, CXCR7 and CXCL12 mRNA expression in HCC. (a) Quantitative reverse transcriptase PCR analysis for CXCR4, CXCR7 and CXCL12 levels in HCC patients. mRNA expression was measured using real-time PCR in normal liver (NL) and HCC. The y-axis values represent the ratio between the value of each gene in HCC/normal liver normalized to GUSB RNA expression. Each assay was performed in triplicate. (b) Relative box plot. (c) Immunohistochemical CXCL12 evaluation. Upper left: peritumoral liver tissue; upper right: HCC tissue (magnification: ×5). Lower left: detail peritumoral liver tissue; lower right: detail HCC tissue (magnification: ×40). HCC, hepatocellular carcinoma; PCR, polymerase chain reaction.
Mentions: To evaluate if the chemokine receptor levels are due to increased transcription, the mRNA levels of CXCR4, CXCR7 and CXCL12 were evaluated in 33/86 frozen tissues using real-time PCR (Figure 3a). CXCR4 mRNA was upregulated in 15/33 (45.5%) HCC patients, and CXCR7 expression was increased in 18/33 (54.5%) patients. In 23/33 (69.7%) HCC patients, CXCR7 was overexpressed compared to CXCR4 (mean fold change 5.5), whereas in 9/33 samples (27.3%), CXCR4 was upregulated (mean fold change 4.4) compared to CXCR7 levels. Interestingly, the ligand CXCL12 was overexpressed in the tumor tissue in only three cases, although in 30/33 (90.9%) cases, CXCL12 was overexpressed in peritumoral tissue (mean fold change: 13.5). In Figure 3b, the relative box-plot demonstrates that CXCL12 expression was significantly different between tumor and peritumoral tissues, with lower expression in tumor tissues (P=0.032). CXCL12 was also evaluated using immunohistochemistry, which confirmed a lower expression level in the tumor tissues compared to peritumoral tissues (Figure 3c).

Bottom Line: When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03).Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032).In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not.

View Article: PubMed Central - PubMed

Affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.

ABSTRACT
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

No MeSH data available.


Related in: MedlinePlus