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Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia.

Koukourakis MI, Giatromanolaki A, Sivridis E, Pitiakoudis M, Gatter KC, Harris AL - Br. J. Cancer (2010)

Bottom Line: Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1α and LDH5, as well as with high histological grade, vascular invasion and nodal involvement.Furthermore, patients with extensive over- or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001).Beclin 1 has an important role in growth and metastasis of colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy/Oncology, Democritus University of Thrace and University General Hospital of Alexandroupolis, Alexandroupolis, 68100, Greece. targ@her.forthnet.gr

ABSTRACT

Introduction: Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1, the mammalian orthologue of the yeast Apg6/Vps30 gene, functions as a scaffold for the formation of autophagosomes.

Materials and method: The immunohistochemical patterns of Beclin 1 expression and their prognostic relevance were studied in formalin-fixed tissues from 155 patients with colorectal adenocarcinoma treated with surgery alone.

Results: Using the weak homogeneous expression of Beclin 1 in normal colonic tissues as a basis for assessing tumours, the following grouping/staining patterns were recognised in colorectal carcinomas: a normal-like pattern in 62 of 155 (40%) cases, an underexpression pattern in 24 of 155 (15.5%) cases, extensive overexpression of Beclin 1 in 33 of 155 (21.3%) tumours and limited overexpression of the protein in 36 of 155 (23.2%) tumours. Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1α and LDH5, as well as with high histological grade, vascular invasion and nodal involvement. Furthermore, patients with extensive over- or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001). Beclin 1 had an independent prognostic relevance in multivariate analysis.

Conclusions: Beclin 1 has an important role in growth and metastasis of colorectal cancer. Loss of Beclin 1 expression (allelic loss or microRNA regulatory activity, as suggested in the literature) defines poor prognosis presumably by promoting anti-apoptotic pathways, while overexpression of the protein, being linked with tumour hypoxia and acidity, also defines subgroups of tumours with aggressive clinical behaviour.

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Immunohistochemical patterns of Beclin 1 expression: (A) Normal colonic tissue showing weak cytoplasmic expression of Beclin 1 in parallel with sporadic staining of nuclei. (B) Normal-like Beclin 1 expression pattern in a colorectal adenocarcinoma. (C) Overexpression of Beclin 1 in the cytoplasm and nuclei of a colorectal adenocarcinoma. (D) Downregulation of Beclin 1 expression in a colorectal adenocarcinoma with sporadic weak staining of nuclei.
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fig1: Immunohistochemical patterns of Beclin 1 expression: (A) Normal colonic tissue showing weak cytoplasmic expression of Beclin 1 in parallel with sporadic staining of nuclei. (B) Normal-like Beclin 1 expression pattern in a colorectal adenocarcinoma. (C) Overexpression of Beclin 1 in the cytoplasm and nuclei of a colorectal adenocarcinoma. (D) Downregulation of Beclin 1 expression in a colorectal adenocarcinoma with sporadic weak staining of nuclei.

Mentions: The intensity and extent of cytoplasmic expression was also recorded in all optical fields. The intensity ranged from negative through weak to strong. The whole tissue section, including tumour and adjacent normal colon area, was examined in all × 200 optical fields available. Given that the normal colonic epithelium consistently showed a weak cytoplasmic expression of Beclin 1, this grade of intensity in tumour cells was considered as ‘normal-like' (Figure 1A). Taking this weak staining as a criterion, there were tumour cells with loss of Beclin 1 expression and those overexpressing the protein. The percentage of cells with normal-like intensity and those with under- or overexpression was recorded in all × 200 optical fields and the mean value was used to score each case. Combining the results of extent and intensity of staining, the tumours were allocated to the following four categories:


Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia.

Koukourakis MI, Giatromanolaki A, Sivridis E, Pitiakoudis M, Gatter KC, Harris AL - Br. J. Cancer (2010)

Immunohistochemical patterns of Beclin 1 expression: (A) Normal colonic tissue showing weak cytoplasmic expression of Beclin 1 in parallel with sporadic staining of nuclei. (B) Normal-like Beclin 1 expression pattern in a colorectal adenocarcinoma. (C) Overexpression of Beclin 1 in the cytoplasm and nuclei of a colorectal adenocarcinoma. (D) Downregulation of Beclin 1 expression in a colorectal adenocarcinoma with sporadic weak staining of nuclei.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967071&req=5

fig1: Immunohistochemical patterns of Beclin 1 expression: (A) Normal colonic tissue showing weak cytoplasmic expression of Beclin 1 in parallel with sporadic staining of nuclei. (B) Normal-like Beclin 1 expression pattern in a colorectal adenocarcinoma. (C) Overexpression of Beclin 1 in the cytoplasm and nuclei of a colorectal adenocarcinoma. (D) Downregulation of Beclin 1 expression in a colorectal adenocarcinoma with sporadic weak staining of nuclei.
Mentions: The intensity and extent of cytoplasmic expression was also recorded in all optical fields. The intensity ranged from negative through weak to strong. The whole tissue section, including tumour and adjacent normal colon area, was examined in all × 200 optical fields available. Given that the normal colonic epithelium consistently showed a weak cytoplasmic expression of Beclin 1, this grade of intensity in tumour cells was considered as ‘normal-like' (Figure 1A). Taking this weak staining as a criterion, there were tumour cells with loss of Beclin 1 expression and those overexpressing the protein. The percentage of cells with normal-like intensity and those with under- or overexpression was recorded in all × 200 optical fields and the mean value was used to score each case. Combining the results of extent and intensity of staining, the tumours were allocated to the following four categories:

Bottom Line: Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1α and LDH5, as well as with high histological grade, vascular invasion and nodal involvement.Furthermore, patients with extensive over- or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001).Beclin 1 has an important role in growth and metastasis of colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy/Oncology, Democritus University of Thrace and University General Hospital of Alexandroupolis, Alexandroupolis, 68100, Greece. targ@her.forthnet.gr

ABSTRACT

Introduction: Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1, the mammalian orthologue of the yeast Apg6/Vps30 gene, functions as a scaffold for the formation of autophagosomes.

Materials and method: The immunohistochemical patterns of Beclin 1 expression and their prognostic relevance were studied in formalin-fixed tissues from 155 patients with colorectal adenocarcinoma treated with surgery alone.

Results: Using the weak homogeneous expression of Beclin 1 in normal colonic tissues as a basis for assessing tumours, the following grouping/staining patterns were recognised in colorectal carcinomas: a normal-like pattern in 62 of 155 (40%) cases, an underexpression pattern in 24 of 155 (15.5%) cases, extensive overexpression of Beclin 1 in 33 of 155 (21.3%) tumours and limited overexpression of the protein in 36 of 155 (23.2%) tumours. Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1α and LDH5, as well as with high histological grade, vascular invasion and nodal involvement. Furthermore, patients with extensive over- or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001). Beclin 1 had an independent prognostic relevance in multivariate analysis.

Conclusions: Beclin 1 has an important role in growth and metastasis of colorectal cancer. Loss of Beclin 1 expression (allelic loss or microRNA regulatory activity, as suggested in the literature) defines poor prognosis presumably by promoting anti-apoptotic pathways, while overexpression of the protein, being linked with tumour hypoxia and acidity, also defines subgroups of tumours with aggressive clinical behaviour.

Show MeSH
Related in: MedlinePlus