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Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer.

Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R, Alabiso O, Arisio R, Katsaros D, Benedetto C, Isidoro C - Biomed Res Int (2014)

Bottom Line: BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death.The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2.The latter inhibits the autophagy function of BECLIN 1.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Anatomy Pathology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100 Novara, Italy.

ABSTRACT
Autophagy is dysregulated in cancer and might be involved in ovarian carcinogenesis. BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death. Induction of autophagy is associated with the presence of vacuoles characteristically labelled with the protein LC3. We have studied the biological and clinical significance of BECLIN 1 and LC3 in ovary tumours of different histological types. The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2. The latter inhibits the autophagy function of BECLIN 1. We found that type I tumours, which are less aggressive than type II, were more frequently expressing high level of BECLIN 1. Of note, tumours of histologic grade III expressed low level of BECLIN 1. Consistently, high level of expression of BECLIN 1 and LC3 in tumours is well correlated with the overall survival of the patients. The present data are compatible with the hypotheses that a low level of autophagy favours cancer progression and that ovary cancer with upregulated autophagy has a less aggressive behaviour and is more responsive to chemotherapy.

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Immunofluorescence staining of LC3 and BCL-2. Selection of representative cases. The histologic type, the positivity for BECLIN 1 aggregates, the clinical outcome (CR: complete remission; DOD: dead of disease), the pathological stage, and the histologic grade are reported. The nuclei are evidenced by DAPI staining.
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fig5: Immunofluorescence staining of LC3 and BCL-2. Selection of representative cases. The histologic type, the positivity for BECLIN 1 aggregates, the clinical outcome (CR: complete remission; DOD: dead of disease), the pathological stage, and the histologic grade are reported. The nuclei are evidenced by DAPI staining.

Mentions: The interaction of BECLIN 1 with BCL-2 abrogates the induction of autophagy [22]. On the other hand, high expression of BCL-2 inhibits not only autophagy but also apoptosis, thus influencing the cytotoxic response of ovarian cancer cells to chemotherapeutics [17, 21]. Thus, evaluating the level of expression of BECLIN 1 may not be sufficient to draw conclusions about the capacity of the cell to activate autophagy. We have analysed by western blotting the expression of BECLIN 1 and of BCL-2 in a small subset of carcinomas for which the frozen biopsy was available (representative cases are shown in Figure 4). In general, the expression of these proteins was inversely related. To seek for a functional relationship between the two proteins, we performed the immunostaining of BECLIN 1, BCL-2, and LC3 in two paradigmatic situations among the cases analysed by western blotting. In case 1, the expression of BCL-2 was quite high, which could account for inhibition of BECLIN 1 proautophagic activity, and in fact this tumour was negative for LC3 staining (Figure 5(a)). On the opposite, BCL-2 and BECLIN 1 were not detectable (by western blotting) in the tumour case 2, and in spite of this the tumour was intensely LC3 positive (Figure 5(b)), which possibly was associated with BECLIN 1-independent autophagy.


Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer.

Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R, Alabiso O, Arisio R, Katsaros D, Benedetto C, Isidoro C - Biomed Res Int (2014)

Immunofluorescence staining of LC3 and BCL-2. Selection of representative cases. The histologic type, the positivity for BECLIN 1 aggregates, the clinical outcome (CR: complete remission; DOD: dead of disease), the pathological stage, and the histologic grade are reported. The nuclei are evidenced by DAPI staining.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127242&req=5

fig5: Immunofluorescence staining of LC3 and BCL-2. Selection of representative cases. The histologic type, the positivity for BECLIN 1 aggregates, the clinical outcome (CR: complete remission; DOD: dead of disease), the pathological stage, and the histologic grade are reported. The nuclei are evidenced by DAPI staining.
Mentions: The interaction of BECLIN 1 with BCL-2 abrogates the induction of autophagy [22]. On the other hand, high expression of BCL-2 inhibits not only autophagy but also apoptosis, thus influencing the cytotoxic response of ovarian cancer cells to chemotherapeutics [17, 21]. Thus, evaluating the level of expression of BECLIN 1 may not be sufficient to draw conclusions about the capacity of the cell to activate autophagy. We have analysed by western blotting the expression of BECLIN 1 and of BCL-2 in a small subset of carcinomas for which the frozen biopsy was available (representative cases are shown in Figure 4). In general, the expression of these proteins was inversely related. To seek for a functional relationship between the two proteins, we performed the immunostaining of BECLIN 1, BCL-2, and LC3 in two paradigmatic situations among the cases analysed by western blotting. In case 1, the expression of BCL-2 was quite high, which could account for inhibition of BECLIN 1 proautophagic activity, and in fact this tumour was negative for LC3 staining (Figure 5(a)). On the opposite, BCL-2 and BECLIN 1 were not detectable (by western blotting) in the tumour case 2, and in spite of this the tumour was intensely LC3 positive (Figure 5(b)), which possibly was associated with BECLIN 1-independent autophagy.

Bottom Line: BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death.The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2.The latter inhibits the autophagy function of BECLIN 1.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Anatomy Pathology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100 Novara, Italy.

ABSTRACT
Autophagy is dysregulated in cancer and might be involved in ovarian carcinogenesis. BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death. Induction of autophagy is associated with the presence of vacuoles characteristically labelled with the protein LC3. We have studied the biological and clinical significance of BECLIN 1 and LC3 in ovary tumours of different histological types. The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2. The latter inhibits the autophagy function of BECLIN 1. We found that type I tumours, which are less aggressive than type II, were more frequently expressing high level of BECLIN 1. Of note, tumours of histologic grade III expressed low level of BECLIN 1. Consistently, high level of expression of BECLIN 1 and LC3 in tumours is well correlated with the overall survival of the patients. The present data are compatible with the hypotheses that a low level of autophagy favours cancer progression and that ovary cancer with upregulated autophagy has a less aggressive behaviour and is more responsive to chemotherapy.

Show MeSH
Related in: MedlinePlus