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CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases.

Mir H, Singh R, Kloecker GH, Lillard JW, Singh S - Oncotarget (2015)

Bottom Line: High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined.Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls.Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA.

ABSTRACT
Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

No MeSH data available.


Related in: MedlinePlus

ADAM 10 expression after CXCL16 stimulation and release of CXCL16 after ADAM 10 inhibition in LuCa cells(A) ADAM 10 mRNA levels by semiquantitative RT-PCR. Copies of transcripts are expressed relative to copies of 18S rRNA. Values are mean ± SEM from 3 independent experiments. ***p ≤ 0.001 compared to SCC (NCI-H520). (B) Protein expression of ADAM 10 after CXCL16 stimulation by flow cytometry. Grey empty histograms represent untreated controls and black filled histograms represent CXCL16 treated sample in SCC (NCI-H520) and AC (NCI-H2126). (C) CXCL16 released after inhibition of ADAM 10 with two different concentrations of GI254023X. CXCL16 levels reduced below detection limit of the kit after inhibition of ADAM 10 in SCC (NCI-H520) cells.
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Figure 6: ADAM 10 expression after CXCL16 stimulation and release of CXCL16 after ADAM 10 inhibition in LuCa cells(A) ADAM 10 mRNA levels by semiquantitative RT-PCR. Copies of transcripts are expressed relative to copies of 18S rRNA. Values are mean ± SEM from 3 independent experiments. ***p ≤ 0.001 compared to SCC (NCI-H520). (B) Protein expression of ADAM 10 after CXCL16 stimulation by flow cytometry. Grey empty histograms represent untreated controls and black filled histograms represent CXCL16 treated sample in SCC (NCI-H520) and AC (NCI-H2126). (C) CXCL16 released after inhibition of ADAM 10 with two different concentrations of GI254023X. CXCL16 levels reduced below detection limit of the kit after inhibition of ADAM 10 in SCC (NCI-H520) cells.

Mentions: Metalloproteinases are known to regulate metastatic processes [32]. Elevated ADAM 10 expression by tumors is shown to be poor prognostic indicator in many cancers [33–37]. It also plays important role in shedding of CXCL16. Interestingly, we found higher levels of ADAM 10 mRNA in SCC as compared to AC cells (Figure 6A). However, ADAM 10 protein was higher in AC cells, than SCC cells (Figure 6B). Soluble CXCL16 levels were significantly reduced in SCC culture supernatants after inhibition of ADAM 10 with its pharmacological inhibitor (GI254023X) (Figure 6C). On the other hand, soluble CXCL16 induced ADAM 10 expression in SCC cells (Figure 6B). However, such interdependence between soluble CXCL16 and ADAM 10 was not observed in AC cells (Figure 6B and 6C).


CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases.

Mir H, Singh R, Kloecker GH, Lillard JW, Singh S - Oncotarget (2015)

ADAM 10 expression after CXCL16 stimulation and release of CXCL16 after ADAM 10 inhibition in LuCa cells(A) ADAM 10 mRNA levels by semiquantitative RT-PCR. Copies of transcripts are expressed relative to copies of 18S rRNA. Values are mean ± SEM from 3 independent experiments. ***p ≤ 0.001 compared to SCC (NCI-H520). (B) Protein expression of ADAM 10 after CXCL16 stimulation by flow cytometry. Grey empty histograms represent untreated controls and black filled histograms represent CXCL16 treated sample in SCC (NCI-H520) and AC (NCI-H2126). (C) CXCL16 released after inhibition of ADAM 10 with two different concentrations of GI254023X. CXCL16 levels reduced below detection limit of the kit after inhibition of ADAM 10 in SCC (NCI-H520) cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496412&req=5

Figure 6: ADAM 10 expression after CXCL16 stimulation and release of CXCL16 after ADAM 10 inhibition in LuCa cells(A) ADAM 10 mRNA levels by semiquantitative RT-PCR. Copies of transcripts are expressed relative to copies of 18S rRNA. Values are mean ± SEM from 3 independent experiments. ***p ≤ 0.001 compared to SCC (NCI-H520). (B) Protein expression of ADAM 10 after CXCL16 stimulation by flow cytometry. Grey empty histograms represent untreated controls and black filled histograms represent CXCL16 treated sample in SCC (NCI-H520) and AC (NCI-H2126). (C) CXCL16 released after inhibition of ADAM 10 with two different concentrations of GI254023X. CXCL16 levels reduced below detection limit of the kit after inhibition of ADAM 10 in SCC (NCI-H520) cells.
Mentions: Metalloproteinases are known to regulate metastatic processes [32]. Elevated ADAM 10 expression by tumors is shown to be poor prognostic indicator in many cancers [33–37]. It also plays important role in shedding of CXCL16. Interestingly, we found higher levels of ADAM 10 mRNA in SCC as compared to AC cells (Figure 6A). However, ADAM 10 protein was higher in AC cells, than SCC cells (Figure 6B). Soluble CXCL16 levels were significantly reduced in SCC culture supernatants after inhibition of ADAM 10 with its pharmacological inhibitor (GI254023X) (Figure 6C). On the other hand, soluble CXCL16 induced ADAM 10 expression in SCC cells (Figure 6B). However, such interdependence between soluble CXCL16 and ADAM 10 was not observed in AC cells (Figure 6B and 6C).

Bottom Line: High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined.Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls.Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA.

ABSTRACT
Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

No MeSH data available.


Related in: MedlinePlus