Rouli Zhou

Expression of LAPTM4B-35: A novel marker of progression, invasiveness and poor prognosis of extrahepatic cholangiocarcinoma☆

LAPTM4B was proven to overexpress in hepatocellular carcinoma and relate to differentiation. We immunohistochemically investigated the expression and potential clinicopathological and prognostic significance of LAPTM4B encoded protein, LAPTM4B-35, in extrahepatic cholangiocarcinoma (EHCC) for specimens from consecutive 81 patients. LAPTM4B-35 staining was positive in cancer tissues from 59 patients (72.8%), including 12 with score 1, 22 with score 2 and 25 with score 3. No positive staining was found in non-cancer epithelia. The staining score in cancer tissues was not only significantly associated with TNM staging, histological grade, perineural and lymph node invasion (P<0.05), but also of comprehensive prognostic implications, including integrated estimation with CA19-9. These data established that LAPTM4B-35 positively expressed in a great portion of EHCC and might be a novel molecular maker of progression, invasiveness and poor prognosis.

Overexpression of LAPTM4B-35 promotes growth and metastasis of hepatocellular carcinoma in vitro and in vivo.

LAPTM4B-35, encoded by Lysosomal protein transmembrane 4 beta (LAPTM4B) is over-expressed in more than 71% of hepatocellular carcinomas (HCCs) and associated with prognosis of the patients. But the exact role and molecular mechanism in HCC have not been determined. In this study, we explored the effects and mechanisms of LAPTM4B-35 on tumor growth and metastasis in vitro and in vivo by overexpression and depletion of LAPTM4B in HCC HepG2 and Bel7402 cells. These findings suggest that overexpression of LAPTM4B-35 plays a critical role in the growth and metastasis of HCC, and LAPTM4B-35 may therefore be a therapeutic target for HCC.

LAPTM4B-35 is a novel prognostic factor of hepatocellular carcinoma.

LAPTM4B‐35 is a 35‐kDa tetra‐transmembrane protein overexpressed in hepatocellular carcinoma (HCC) and promotes cell survival, proliferation, and tumorigenesis. However, the potential clinical implications of LAPTM4B‐35 in HCC are still unclear. This study is aimed to investigate the correlations between LAPTM4B‐35 expression and prognosis in patients with HCC.

Over‐expression of LAPTM4B is associated with poor prognosis and chemotherapy resistance in stages III and IV epithelial ovarian cancer

The purpose of this study was to determine whether LAPTM4B over‐expression is associated with the prognosis and chemotherapy resistance in patients with stages III and IV epithelial ovarian carcinoma, i.e., patients with peritoneal metastasis or lymph node metastasis of epithelial ovarian carcinoma.

Overexpression of LAPTM4B promotes growth of gallbladder carcinoma cells in vitro

BACKGROUND The overexpression of LAPTM4B-35 in gallbladder carcinoma (GBC) and its clinicopathologic and prognostic significance have been previously shown. Thus, this gene may play a role in the growth of GBC cells. METHODS The pcDNA3-AE containing the complete open reading frame of LAPTM4B (lysosome-associated protein transmembrane-4beta) and mock (pcDNA3) plasmids were transiently transfected into GBC-SD cells. Cell proliferation, cell cycle distribution, and protein expression were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium assay, flow cytometry, and Western blot, respectively. RESULTS Cells transfected with pcDNA3-AE revealed accelerated proliferation, less serum dependence, and significant cell cycle progression compared with cells transfected with mock plasmid and parent cells. These phenotypes were accompanied by upregulated expression of C-myc, c-Fos, c-Jun, cyclin D1, and cyclin E and downregulated expression of P16 and P-27. CONCLUSIONS LAPTM4B overexpression promotes the growth of GBC cells in vitro by regulating the expression levels of some proliferation-associated proteins. Therefore, the LAPTM4B gene might be used as a novel therapeutic target of GBC.

Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells

BACKGROUND It was shown previously that LAPTM4B promoted growth of gallbladder carcinoma (GBC) cells and predicted poor prognosis in GBC; however, its roles and relative mechanisms in apoptosis of GBC cells remain unknown. METHODS The plasmids, pcDNA3-AE, containing the complete open reading frame of LAPTM4B and Mock (pcDNA3), were transfected transiently into GBC-SD cells, followed by induction of apoptosis by epirubicin. Cell apoptosis was determined by Hoechst 33258 staining, propidium iodide (PI) staining, and Annexin V/PI double staining flow cytometry. Protein expression was detected by immunoblotting. RESULTS Overexpression of LAPTM4B-35 was observed in cells transfected with pcDNA3-AE. These cells possessed significantly less apoptosis ratios compared with cells transfected with the Mock plasmid, although the values were still greater than those in parent cells. Of the apoptosis-related molecules, expression of Bcl-2 and Bcl-xL was up-regulated in cells transfected with pcDNA3-AE, whereas expressions of Bax, Bid, and cleaved caspase-9 and -3 were down-regulated compared with their expression in other kinds of cells. CONCLUSION Our data show that LAPTM4B-35 attenuated epirubicin-induced apoptosis of GBC-SD cells in vitro through a mitochondria-dependent pathway. Therefore, the protein LAPTM4B-35 might be associated with the chemoresistance of GBC.

LAPTM4B Polymorphisms is Associated with Ovarian Cancer Susceptibility and Its Prognosis

OBJECTIVE Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is an important novel gene associated with the proliferation and differentiation of cells. Recent studies have shown that it was overexpressed in many cancer tissues. This study investigated the association between different LAPTM4B polymorphisms and the susceptibility and prognosis of ovarian cancer. METHODS A case-control study was performed in 282 patients with ovarian cancer and 365 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction. RESULTS There was a significantly higher LAPTM4B 2 allele frequency in ovarian cancer cases than controls (P < 0.05). Using the LAPTM4B 1/1 genotype as the reference, we found that the LAPTM4B 1/2 and LAPTM4B 2/2 genotypes were positively associated with ovarian cancer. Additionally, we found a negative correlation between the tumor grade and LAPTM4B allele genotype, which indicates strongly that LAPTM4B 2 could affect the survival of patients. CONCLUSIONS These findings indicate that the LAPTM4B 2 allele may be a risk factor for ovarian cancer and may play an important role in genetic susceptibility to ovarian cancer.

Overexpression of LAPTM4B-35 in Cervical Carcinoma: A Clinicopathologic Study

Lysosome-associated protein transmembrane 4&bgr;-35 (LAPTM4B-35) is a member of the mammalian 4-tetratransmembrane spanning protein superfamily, which is overexpressed in several solid malignancies. However, the expression of LAPTM4B-35 and its role in the progression of cervical carcinoma is unknown. The aim of this study was to determine the level of expression of LAPTM4B-35 in cervical carcinoma. Immunohistochemistry was used to determine the expression of LAPTM4B-35 protein in 53 cervical intraepithelial neoplasias (CINs) and 113 cervical carcinomas in comparison with 20 normal cervical specimens. The correlation between the expression of the LAPTM4B-35 protein and the clinicopathologic characteristics of patients with cervical carcinoma was analyzed. Statistical analysis showed that LAPTM4B-35 expression was significantly elevated in CINII/III and cervical carcinoma but not in CINI compared with the normal controls (P=0.002, P<0.001 and P=0.289, respectively). In addition, the LAPTM4B-35 expression was significantly higher in both the CINII/III and cervical carcinoma cases than in the CINI cases (P=0.021 and P=0.002, respectively). High LAPTM4B-35 staining was present in 72.57% (82 of 113) of all the cases with cervical carcinoma. The overexpression of LAPTM4B-35 was significantly associated with the International Federation of Gynecology and Obstetrics stage (P=0.014), tumor histologic grade (P=0.033), lymph node metastasis (P=0.045), and recurrence (P=0.010). The Kaplan-Meier survival analysis showed that the high expression of LAPTM4B-35 was related to the poor overall survival and disease-free survival of patients with cervical carcinoma (P=0.004 and P=0.005, respectively). Multivariate Cox analysis showed that LAPTM4B-35 was an independent factor for both overall survival and disease-free survival (P=0.015 and P=0.016, respectively). Overexpression of LAPTM4B-35 may be associated with tumor progression in cervical carcinoma and thus may serve as a new molecular marker to predict the prognosis of cervical carcinoma patients.

LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis

Abstract A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4 beta) plays several crucial roles in carcinogenesis. In this case-control study, we investigated the relationship between LAPTM4B gene polymorphism and susceptibility to endometrial carcinoma (EC). In an adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes respectively exhibited 1.572-fold (95% confidence interval (CI) = 1.041–2.375) and 2.335-fold (95% CI = 1.365–3.995) increases in the risk of developing EC relative to those carrying LAPTM4B*1/1. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both p < 0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both p < 0.001). These results suggest that LAPTM4B polymorphisms might play an important role in the aetiology of EC.

Combined lysosomal protein transmembrane 4 beta-35 and argininosuccinate synthetase expression predicts clinical outcome in hepatocellular carcinoma patients

PurposeThe newly-identified lysosomal protein transmembrane 4 beta-35 (LAPTM4B-35) plays important roles in tumor progression and metastasis, while argininosuccinate synthetase (ASS) provides arginine as an indispensable nutrient for hepatocellular carcinoma (HCC). The present study investigated the clinical significance of the coexpression of LAPTM4B-35 and ASS in HCC patients on determining the prognosis.MethodsImmunohistochemistry was used to evaluate the expression of LAPTM4B-35 and ASS in HCC tissues and paired noncancerous liver samples from 71 patients. The correlation of combined LAPTM4B-35 and ASS expression with selected clinicopathologic parameters was assessed with the chi-squared test. Patient survival and differences in survival were determined by the Kaplan-Meier method and the log-rank test. A Cox regression analysis was adopted for a multivariate analysis of the prognostic factors.ResultsCombined LAPTM4B-35 and ASS expression was significantly associated with TNM stage and portal vein invasion. In addition, patients with HCCs expressing both LAPTM4B-35 and ASS exhibited both markedly poorer overall survival (OS) and disease-free survival (DFS) (both P < 0.001). According to the multivariate analyses, combined LAPTM4B-35 and ASS expression was found to be an independent prognostic factor for OS and DFS (P = 0.039 and P = 0.035, respectively).ConclusionThe overexpression of LAPTM4B-35 in combination with positive ASS expression is a negative prognostic marker for HCC.