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Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis.

Wang HC, Chiang WF, Huang HH, Shen YY, Chiang HC - BMC Cancer (2014)

Bottom Line: We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells.Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones.In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No,35, Keyan Road, Zhunan, 35053 Miaoli County, Taiwan. hcchiang@nhri.org.tw.

ABSTRACT

Background: Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis.

Methods: SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo.

Results: We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA.

Conclusions: Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.

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Related in: MedlinePlus

SHP2 promotes lung metastasis. SHP2 si-RNA delivered via tail vein injection dramatically reduced the metastatic capacity of HSC3 cells. Representative images showing H&E staining of lung tissues were taken under bright-field at 200× using a scanning microscope (Upper panel). Black lines delineate tumor tissue (T). Quantitative metastasis index was indicated as mean ± SD. *, P < 0.05 compared with the control group, HSC3 cells (Lower panel).
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Figure 5: SHP2 promotes lung metastasis. SHP2 si-RNA delivered via tail vein injection dramatically reduced the metastatic capacity of HSC3 cells. Representative images showing H&E staining of lung tissues were taken under bright-field at 200× using a scanning microscope (Upper panel). Black lines delineate tumor tissue (T). Quantitative metastasis index was indicated as mean ± SD. *, P < 0.05 compared with the control group, HSC3 cells (Lower panel).

Mentions: We evaluated the effects of SHP2 attention on the metastasis of oral cancer cells toward the lung to establish the potential for developing SHP2 as a target for human oral cancer treatment. As shown in Figure 5, we analyzed the lungs of mice with HSC3 xenografts and SHP2 si-RNA administered through tail vein injection by using H&E staining. Analysis of lung tissue sections indicated that HSC3 tumors with SHP2 knockdown exhibited an approximate 70% reduction in metastatic capacity, compared with those with control si-RNA (Figure 5, lower panel). Overall, the result supported that SHP2 inhibits the migration, invasion, and metastasis of oral cancer cells, and indicated that SHP2 is a potential target for oral cancer treatment.


Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis.

Wang HC, Chiang WF, Huang HH, Shen YY, Chiang HC - BMC Cancer (2014)

SHP2 promotes lung metastasis. SHP2 si-RNA delivered via tail vein injection dramatically reduced the metastatic capacity of HSC3 cells. Representative images showing H&E staining of lung tissues were taken under bright-field at 200× using a scanning microscope (Upper panel). Black lines delineate tumor tissue (T). Quantitative metastasis index was indicated as mean ± SD. *, P < 0.05 compared with the control group, HSC3 cells (Lower panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4067087&req=5

Figure 5: SHP2 promotes lung metastasis. SHP2 si-RNA delivered via tail vein injection dramatically reduced the metastatic capacity of HSC3 cells. Representative images showing H&E staining of lung tissues were taken under bright-field at 200× using a scanning microscope (Upper panel). Black lines delineate tumor tissue (T). Quantitative metastasis index was indicated as mean ± SD. *, P < 0.05 compared with the control group, HSC3 cells (Lower panel).
Mentions: We evaluated the effects of SHP2 attention on the metastasis of oral cancer cells toward the lung to establish the potential for developing SHP2 as a target for human oral cancer treatment. As shown in Figure 5, we analyzed the lungs of mice with HSC3 xenografts and SHP2 si-RNA administered through tail vein injection by using H&E staining. Analysis of lung tissue sections indicated that HSC3 tumors with SHP2 knockdown exhibited an approximate 70% reduction in metastatic capacity, compared with those with control si-RNA (Figure 5, lower panel). Overall, the result supported that SHP2 inhibits the migration, invasion, and metastasis of oral cancer cells, and indicated that SHP2 is a potential target for oral cancer treatment.

Bottom Line: We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells.Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones.In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No,35, Keyan Road, Zhunan, 35053 Miaoli County, Taiwan. hcchiang@nhri.org.tw.

ABSTRACT

Background: Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis.

Methods: SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo.

Results: We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA.

Conclusions: Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.

Show MeSH
Related in: MedlinePlus