Prognostic Significance of α5β1-integrin Expression in Cervical Cancer

Abstract

Asian Pacific J Cancer Prev, 14 (6), 3891-3895 IntroductionCervical cancer (CC) is the second most common malignant diseases of women in the world. More than 500,000 new cases of cervical cancer were reported each year worldwide, of which approximately 1/3 from China mainland. So, cervical cancer is a cause of significant morbidity and cancer-related mortality in China women. With the improvement of modern irradiation techniques and development of novel drugs, cervical cancer remains an unsolved problem of oncology both due to the increased rate of local failures and of the distant metastasis. Although the death rate for cervical cancer has decreased dramatically since the introduction of cervical cytology as a widespread screening procedure, the survival rate at advanced stages of disease has not improved. Therefore, characterization of identifiable molecular markers may play an important role in understanding of molecular pathogenesis and in identifying latently prognostic biomarkers for cervical cancer.Numerous studies demonstrated that α5β1-integrin expression levels are altered in many types of cancer (Morozevich et al., 2009), there may be involved in modulating effect on several signalling pathways ,which are closely related to the regulation of cell survival, proliferation ,differentiation and apoptosis, and in stimulating tumor angiogenesis (Zeng et al., 2009) Although it has been shown that α5β1-integrin AbstractThe purpose of this study was to evaluate the association of expression of α5β1-integrin with clinicopathologic features and prognosis in cervical cancer. Levels of α5β1-integrin in normal cervical mucosa and cervical cancer tissue were detected with immunohistochemistry. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. α5β1-integrin expression was detected in 84.6% (143/169) cervical cancer samples, significantly different from that in normal cervical mucosa (P < 0.05). Positive expression rates of α5β1-integrin in patients with poor histologic differentiation, lymph node metastasis, and recurrence were elevated. Using Kaplan-Meier analysis, a comparison of survival curves of low versus high expression of α5β1-integrin revealed a highly significant difference in human cervical cancer cases (P < 0.05), suggesting that overexpression of α5β1-integrin is associated with a worse prognosis.The α5β1-integrin promotes angiogenesis and associates with lymph node metastasis, vascular invasion and poor prognosis of cervical cancer. The current study indicated that α5β1-integrin may be an independent prognostic factor for cervical cancer patients.

Development of the Fibronectin–Mimetic Peptide KSSPHSRN(SG)₅RGDSP as a Novel Radioprobe for Molecular Imaging of the Cancer Biomarker α₅β₁ Integrin

“…The PR_b peptide, KSSPHSRN(SG) 5 RGDSP was synthesized by the standard 9-fluorenylmethoxycarbonyl (Fmoc)-based solid phase method using an Applied Biosystems 433 A peptide synthesizer. Deblocking of the protected peptide was carried out in a solution containing trifluoroacetic acid (TFA), thioanisole, ethanedithiol, phenol, and water at room temperature (RT) for 2 h. For 18 F-labeling, one β-alanine was added to the N-terminus of PR_b to produce the sequence β-Ala-KSSPHSRN(SG) 5 RGDSP, which was then conjugated at the N-terminus with the chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA, Macrocyclics Inc., Dallas, TX, U.S.A.).…”

“…Deblocking of the protected peptide was carried out in a solution containing trifluoroacetic acid (TFA), thioanisole, ethanedithiol, phenol, and water at room temperature (RT) for 2 h. For 18 F-labeling, one β-alanine was added to the N-terminus of PR_b to produce the sequence β-Ala-KSSPHSRN(SG) 5 RGDSP, which was then conjugated at the N-terminus with the chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA, Macrocyclics Inc., Dallas, TX, U.S.A.). In brief, this peptide resin (0.1 mmol), dissolved in N,N-dimethylformamide (DMF, 5 mL) with triethylamine (10 µL), was reacted with p-SCN-Bn-NOTA (0.15 mmol) in DMF (1 mL) at RT for 12 h, and followed by the above-mentioned deblocking procedure.…”

“…1) Suppression of α 5 β 1 activities has been shown to potentiate the efficacy of chemo-or radiotherapy and induce apoptosis. 2,3) Overexpression of α 5 β 1 revealed that it had prognostic value for patients with non-small cell lung cancer, 4) colorectal cancer, 5) cervical cancer, 6) and gastric cancer. 7) A number of α 5 β 1 antagonists including antibodies, peptides, and small nonpeptidic molecules have been developed as therapeutic agents, and some are in clinical trials.…”

“…10,11) PR_b, KSSPHSRN(SG) 5 RGDSP, is an α 5 β 1 -specific fibronectinmimetic peptide developed by Kokkoli and colleagues.…”

“…12) The presence of (SG) 5 was designed to closely mimic both the distance and the hydrophobicity/hydrophilicity between PHSRN and RGD in native fibronectin, while the motif KSS served as a spacer for functional conjugation. 12,13) The binding affinity of the PR_b ligand to the isolated α 5 β 1 receptor was determined to have a dissociation constant, K d , of 0.0763±0.0063 µM, which is strikingly stronger than that of the GRGDSP peptide (K d , 270±353 µM), and only moderately weaker than that of the fibronectin (K d , 0.03 µM).…”