Overexpression of LAPTM4B-35 closely correlated with clinicopathological features and post-resectional survival of gallbladder carcinoma

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Abstract

Gallbladder carcinoma (GBC) is a malignancy with dismal prognosis and unclear gene expression profile. We aimed to first present the expression of LAPTM4B-35, one product of a cancer associated gene recently cloned in hepatocellular carcinoma (HCC), and its correlation with clinicopathological features and prognosis of GBC. Immunohistochemical detection of LAPTM4B-35 was performed on samples from 75 patients with GBC. LAPTM4B-35 protein was overexpressed in 57 patients (76%) with GBC. The staining scores were significantly related to histology type, lymph node involvement, distant metastasis, Nevin staging and differentiation of GBC (P < 0.05). Univariate analysis revealed that overall or disease-free survival of patients was inversely associated with its staining scores (P < 0.001). Multivariate analysis showed that LAPTM4B-35 staining score was an independent prognostic marker for both overall and disease-free post-resectional survival of GBC (P = 0.004 and 0.027, respectively). LAPTM4B-35 overexpressed in a majority of GBCs and correlated with clinicopathological features and post-resectional survival.

Introduction

Gallbladder carcinoma (GBC) is a malignancy with extensively poor prognosis.1, 2 Although GBC used to be identified as a relatively uncommon tumour, its higher or increased incidence was reported in some populations,3, 4, 5, 6 including residents in some areas of China. Epidemiological data showed that incidence of GBC had a 140% increase in men and 126% in women in urban Shanghai.6 Therefore, many studies focused on genes and their products involved in different stages of gallbladder carcinogenesis, such as p53,7 K-ras,8 β-catenin,9 cyclin D1,10 p27Kip1,11 mucins and cytokeratins.12 Besides, some of them were shown to be of prognostic significance.10, 11 However, further comprehensive investigations and new clues were expected.

Recently, a novel gene, overexpressed in hepatocellular carcinoma (HCC) and designated by HUGO as LAPTM4B (lysosome-associated protein transmembrane-4 beta), was successfully cloned by fluorescence differential display, rapid amplification of cDNA ends (RACE) and RT-PCR.13, 14 It has been clarified that LAPTM4B gene is mapped to chromosome 8q22.1, with seven exons separated by six introns.14 Interestingly, LAPTM4B gene encoded two proteins with different molecular weight, 35 kDa and 24 kDa.15 Experiments revealed that expression of LAPTM4B, at both mRNA and protein levels, was highly upregulated in most specimens and inversely correlated with differentiation of HCC.14, 15, 16 What calls for special attention is that the main protein overexpressed in HCC is LAPTM4B-35.15, 16 Current data showed that LAPTM4B was also remarkably expressed in several cancers, such as breast cancer, lung cancer, gastric cancer, colon cancer, uterus cancer, ovary cancer, adrenocorticotrophin (ACTH)-secreting and non-functioning pituitary adenoma, but not commonly expressed in oesophageal and rectum cancers.16, 17, 18 However, there has not been any evidence concerning its expression status in GBC, so far. Furthermore, clinicopathological relevance and significance of LAPTM4B overexpression in GBC remain unknown.

The present study aims to show expression of LAPTM4B-35 in GBC and to investigate its relationship to clinicopathological features and its impact on post-resectional survival.

Section snippets

Patients

Matched cancerous tissues and adjacent non-cancerous gallbladder epithelia were obtained from 75 consecutive patients with GBC undergoing surgery in our institution from 1991 to 2002. There were 49 females and 26 males (median age, 62 years; range, 30–88 years). Histological type, lymph node involvement and differentiation grade for GBC were determined with routine pathological examination after surgery. Distant metastases were found by imaging examinations and confirmed during operation. All

Expression of LAPTM4B-35 and its relationship with clinicopathological features of GBC

Overexpression of LAPTM4B-35 was found in specimens from 57 patients (76%) with GBC, according to abovementioned criteria (Fig. 1). Nine, 27 and 21 overexpressed cancerous samples were exhibited with staining scores 1, 2 and 3, respectively. The staining score significantly correlated with histology type, lymph node involvement, distant metastasis, Nevin staging and differentiation of GBC (P < 0.05; Table 1), but not with age, sex, tumour size and serum level of tumour antigen markers (P > 0.05,

Discussion

Gallbladder carcinoma (GBC) was generally recognised as a life-threatening malignancy because of its dismal prognosis,20 although it was obviously improved through radical resection according to some authors.21 Therefore, many molecules involved in gallbladder carcinogenesis have been identified in published papers7, 8, 9, 10, 11, 12 and more clues are still expected. To our best knowledge, this is the first report referring expression and significance of LAPTM4B, a gene first cloned in HCC, in

Conflict of interest statement

None declared.

Acknowledgement

The authors thank Professor Rou-Li Zhou for kindly providing LAPTM4B-N1-99-pAb. We also thank Dr. Yu-Feng Luo for her technical support.

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