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MiR-34a suppresses amphiregulin and tumor metastatic potential of head and neck squamous cell carcinoma (HNSCC).

Zhang J, Wang Y, Chen X, Zhou Y, Jiang F, Chen J, Wang L, Zhang WF - Oncotarget (2015)

Bottom Line: We demonstrated that the mRNA and protein levels of AREG were greatly reduced when forcing miR-34a expression.Moreover, the results of luciferase assay provided the further evidence that miR-34a degraded AREG mRNA through targeting the 3'-UTR site.Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei_MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.

ABSTRACT
MiR-34a is a well-known tumor metastasis inhibitor, but only a few target genes involved in metastasis have been identified. In HNSCC, the role of miR-34a in metastasis has not been fully elaborated, and the target gene of miR-34a is still blind. Here we addressed that, the relative lower expression of miR-34a is associated with HNSCC lymphatic metastasis. HNSCC metastasis was found to be strongly suppressed in vitro and in vivo by over-expressing miR-34a. In order to screen the possible target genes of miR-34a in HNSCC, a microarray-based differential mRNA profiling mediated by miR-34a over-expression was performed, and AREG was identified as a pivotal target. We demonstrated that the mRNA and protein levels of AREG were greatly reduced when forcing miR-34a expression. The correlation between AREG mRNA levels and HNSCC metastatic phenotype was also significant in HNSCC tissues (p < 0.01). Moreover, the results of luciferase assay provided the further evidence that miR-34a degraded AREG mRNA through targeting the 3'-UTR site. Restoration of AREG expression partially rescued miR-34a-mediated cell invasion defects in vivo and in vitro. Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG. Taken together, these findings indicate that miR-34a targets AREG, and is essential in inhibition of HNSCC metastasis.

No MeSH data available.


Related in: MedlinePlus

MiR-34a reduced metastatic potential of HNSCC cells in vivo(A) The macroscopy of metastasis nodes induced by Fadu-miR-34a and Fadu-control in the lung of nude mice. (B) The weights of mice lungs with metastasis nodes induced by Fadu-miR-34a and control cells (p < 0.01). (C) The histopathology of metastases induced by Fadu-miR-34a and Fadu-control in lung tissues with HE staining (Original magnifications × 100). *necrotic area.
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Figure 3: MiR-34a reduced metastatic potential of HNSCC cells in vivo(A) The macroscopy of metastasis nodes induced by Fadu-miR-34a and Fadu-control in the lung of nude mice. (B) The weights of mice lungs with metastasis nodes induced by Fadu-miR-34a and control cells (p < 0.01). (C) The histopathology of metastases induced by Fadu-miR-34a and Fadu-control in lung tissues with HE staining (Original magnifications × 100). *necrotic area.

Mentions: To testify whether ectopic miR-34a could inhibit cell metastasis in vivo, Fadu cells over expressing miR-34a or transfected with control vector were injected into the tail vein of nude mice. Two months after tail vein injection, a dramatic effect on the size of eventually formed lesions and the weight of lung with metastases were observed. Fadu-miR-34a generated fine and scattered metastatic nodes, while the control cells (Fadu-miR-control) resulted in massive and confluent metastatic nodes (Figure 3A). Statistical analysis showed that the weights of mice lungs with metastatic nodes from Fadu-miR-34a cells shrunk about 1.5-fold compared with that from control cells (Figure 3B). The pathological changes of the bilateral lungs with HE staining were observed through light microscope at the same time. The tumor nests derived from control cells exhibited large area of lung tissue destruction and/or necrosis, while cells over-expressing miR-34a formed smaller and fewer tumor nests (Figure 3C).


MiR-34a suppresses amphiregulin and tumor metastatic potential of head and neck squamous cell carcinoma (HNSCC).

Zhang J, Wang Y, Chen X, Zhou Y, Jiang F, Chen J, Wang L, Zhang WF - Oncotarget (2015)

MiR-34a reduced metastatic potential of HNSCC cells in vivo(A) The macroscopy of metastasis nodes induced by Fadu-miR-34a and Fadu-control in the lung of nude mice. (B) The weights of mice lungs with metastasis nodes induced by Fadu-miR-34a and control cells (p < 0.01). (C) The histopathology of metastases induced by Fadu-miR-34a and Fadu-control in lung tissues with HE staining (Original magnifications × 100). *necrotic area.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480692&req=5

Figure 3: MiR-34a reduced metastatic potential of HNSCC cells in vivo(A) The macroscopy of metastasis nodes induced by Fadu-miR-34a and Fadu-control in the lung of nude mice. (B) The weights of mice lungs with metastasis nodes induced by Fadu-miR-34a and control cells (p < 0.01). (C) The histopathology of metastases induced by Fadu-miR-34a and Fadu-control in lung tissues with HE staining (Original magnifications × 100). *necrotic area.
Mentions: To testify whether ectopic miR-34a could inhibit cell metastasis in vivo, Fadu cells over expressing miR-34a or transfected with control vector were injected into the tail vein of nude mice. Two months after tail vein injection, a dramatic effect on the size of eventually formed lesions and the weight of lung with metastases were observed. Fadu-miR-34a generated fine and scattered metastatic nodes, while the control cells (Fadu-miR-control) resulted in massive and confluent metastatic nodes (Figure 3A). Statistical analysis showed that the weights of mice lungs with metastatic nodes from Fadu-miR-34a cells shrunk about 1.5-fold compared with that from control cells (Figure 3B). The pathological changes of the bilateral lungs with HE staining were observed through light microscope at the same time. The tumor nests derived from control cells exhibited large area of lung tissue destruction and/or necrosis, while cells over-expressing miR-34a formed smaller and fewer tumor nests (Figure 3C).

Bottom Line: We demonstrated that the mRNA and protein levels of AREG were greatly reduced when forcing miR-34a expression.Moreover, the results of luciferase assay provided the further evidence that miR-34a degraded AREG mRNA through targeting the 3'-UTR site.Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei_MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.

ABSTRACT
MiR-34a is a well-known tumor metastasis inhibitor, but only a few target genes involved in metastasis have been identified. In HNSCC, the role of miR-34a in metastasis has not been fully elaborated, and the target gene of miR-34a is still blind. Here we addressed that, the relative lower expression of miR-34a is associated with HNSCC lymphatic metastasis. HNSCC metastasis was found to be strongly suppressed in vitro and in vivo by over-expressing miR-34a. In order to screen the possible target genes of miR-34a in HNSCC, a microarray-based differential mRNA profiling mediated by miR-34a over-expression was performed, and AREG was identified as a pivotal target. We demonstrated that the mRNA and protein levels of AREG were greatly reduced when forcing miR-34a expression. The correlation between AREG mRNA levels and HNSCC metastatic phenotype was also significant in HNSCC tissues (p < 0.01). Moreover, the results of luciferase assay provided the further evidence that miR-34a degraded AREG mRNA through targeting the 3'-UTR site. Restoration of AREG expression partially rescued miR-34a-mediated cell invasion defects in vivo and in vitro. Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG. Taken together, these findings indicate that miR-34a targets AREG, and is essential in inhibition of HNSCC metastasis.

No MeSH data available.


Related in: MedlinePlus