Gene Expression Profiling Identified High-mobility Group AT-hook 2 (HMGA2) as Being Frequently Upregulated in Esophageal Squamous Cell Carcinoma

Leo C. M. Cheung, Kenneth K. Y. Lai, Alfred K. Y. Lam, Johnny C. O. Tang, John M. Luk, Nikki P. Lee, Yvonne Chung, Daniel K. H. Tong and Simon Law

Abstracts

Background: Esophageal cancer is one of the most deadly malignancies worldwide and esophageal squamous cell carcinoma (ESCC) is the most frequent type.
Methods: We identified up-regulated genes from gene expression profiles of HKESC-4 cell line, its parental tumor tissues, non-tumoral esophageal epithelia and lymph nodes with metastatic carcinoma using Human Genome U133 Plus 2.0 microarray.
Results: Four genes [High-mobility group AT-hook 2 (HMGA2), paternally expressed 10 (PEG10), SH3 and multiple ankyrin repeat domains 2 (SHANK2) and WNT1 inducible signaling pathway protein 3 (WISP3)] were selected for further validation with real-time quantitative polymerase chain reaction (qPCR) in a panel of ESCC cell lines and clinical specimens. HMGA2 was found to be overexpressed in the panel of ESCC cell lines tested. By using immunohistochemistry, HMGA2 was found to be up-regulated in 70% of ESCC tissues (21 out of 30 cases).
Conclusion: This study demonstrates successful use of gene microarray to identify and reveal HMGA2 as a novel and consistently overexpressed gene in ESCC cell lines and clinical samples.

- See more at: http://www.sciencedomain.org/abstract.php?iid=177&id=12&aid=963#.U3QoeGcU9LM 

Clinical correlation of nuclear survivin in esophageal squamous cell carcinoma

Hui MK, Lai KK, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LC, Srivastava G, Tsao SW, Tang JC, Law S.

Abstract

To examine the correlation of survivin (both total and nuclear survivin) with clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) patients. Tumors and non-tumor tissues near the proximal resection margins were resected from ESCC patients undergone esophagectomy. Quantitative polymerase chain reaction (qPCR) was performed to detect survivin mRNA expression level in the 10 paired tumor and adjacent non-tumor tissues. To confirm with the clinical situation, survivin mRNA and protein expression were measured by qPCR and immunoblot, respectively, in 5 ESCC cell lines and a non-neoplastic esophageal epithelial cell line. Immunohistochemistry was employed to reveal the cellular localization of survivin in tumor tissues isolated from the 64 ESCC patients undergone surgery alone. Up-regulation of survivin mRNA and protein was found in 5 ESCC lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4, and SLMT-1) when compared to a non-neoplastic esophageal epithelial cell line NE-1. In particular, HKESC-3, HKESC-4, and SLMT-1 cells demonstrated ~50-fold increase in survivin mRNA. High level of survivin mRNA in tumor tissues when compared to non-tumor tissues was found in 70 % (7 of 10) of clinical cases. The increase in expression ranged from ~twofold to ~16-fold. Immunohistochemistry results showed that survivin was found at the cell nuclei in all specimens examined. Nuclear expression of survivin was inversely associated with the likelihood of developing nodal metastasis (p = 0.021) and significantly associated with early-stage ESCC (p = 0.039). Nuclear survivin could serve as a marker for indicating disease status in ESCC patients.

PMID: 22528514 [PubMed - indexed for MEDLINE] PMCID: PMC3505527

Cytoplasmic Forkhead Box M1 (FoxM1) in Esophageal Squamous Cell Carcinoma Significantly Correlates with Pathological Disease Stage

Hui MK, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LC, Srivastava G, Tsao SW, Tang JC, Law S.

Abstract

Esophageal cancer is a deadly cancer with esophageal squamous cell carcinoma (ESCC) as the major type. Until now there has been a lack of reliable prognostic markers for this malignancy. This study aims to investigate the clinical correlation between Forkhead box M1 (FoxM1)and patients' parameters in ESCC.

METHODS:

Immunohistochemistry was performed to investigate the expression and localization of FoxM1 in 64ESCC tissues and 10 nontumor esophageal tissues randomly selected from 64 patients before these data were used for clinical correlations.

RESULTS:

Cytoplasmic and nuclear expressions of FoxM1 were found in 63 and 16 of the 64 ESCC tissues, respectively.Low cytoplasmic expression of FoxM1 was correlated with early pathological stage in ESCC (P = 0.018),while patients with nuclear FoxM1 were younger in age than those without nuclear expression (P\0.001).Upregulation of FoxM1 mRNA was found in five ESCCcell lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4,and SLMT-1) when compared to non-neoplastic esophageal squamous cell line NE-1 using quantitative polymerase chain reaction (qPCR). Except for HKESC-3, all studied ESCC cell lines demonstrated a high expression of FoxM1 protein using immunoblot. A high mRNA level of FoxM1 was observed in all of the ESCC tissues examined when compared to their adjacent nontumor tissues using qPCR.

CONCLUSION:

Cytoplasmic FoxM1 was correlated with pathological stage and might be a biomarker for advanced ESCC.

PMID: 21976009 [PubMed - indexed for MEDLINE] PMCID: PMC3243851

Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma

Hui MK, Lai KK, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LC, Srivastava G, Tsao SW, Tang JC, Law S.

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. RON is a transmembrane receptor overexpressed in various cancers; however, the clinical significance of its phosphorylated form (pRON) is not fully deciphered. This report is the first to investigate the expression and clinical significance of pRON in human ESCC. Quantitative polymerase chain reaction revealed an up-regulation of RON mRNA in 70% (7/10) of ESCC tissues when compared to the adjacent nontumor tissues. An overexpression of pRON protein was found in most of the ESCC cell lines studied (4/5) when compared to two non-neoplastic esophageal epithelial cells using immunoblot. In 64 ESCC tissues, pRON was localized at the cell membrane, cytoplasm and nucleus in 15 (23.4%), 63 (98.4%) and 61 (95.3%) cases using immunohistochemistry. Patients having high expression of cytoplasmic pRON significantly associated with shorter median survival when compared to those with low expression (25.41 months vs. 14.43 months), suggesting cytoplasmic pRON as a potential marker for poor prognosis in ESCC patients.

PMID: 22086736 [PubMed - indexed for MEDLINE] 

RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo

Chen Y, Xie D, Yin Li W, Cheung CM, Yao H, Chan CY, Chan CY, Xu FP, Liu YH, Sung JJ, Kung HF.

Abstract

The function of EZH2 in tumorigenesis and liver metastasis of pancreatic cancer has never been elucidated in vivo. EZH2 was overexpressed in pancreatic carcinomas and its overexpression was associated with tumor differentiation and pT status. Suppression of EZH2 caused a significant growth inhibition of pancreatic cancer cells in vitro and markedly diminished their tumorigenicity in vivo. Knock-down of EZH2 inhibited liver metastasis of pancreatic cancer in vivo. EZH2 has a crucial role in tumor growth and liver metastasis of pancreatic cancer.

PMID: 20684863 [PubMed - indexed for MEDLINE] 

Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line HKESC-4 of Chinese origin

Cheung LC, Tang JC, Lee PY, Hu L, Guan XY, Tang WK, Srivastava G, Wong J, Luk JM, Law S.

Abstract

A new human esophageal cancer cell line, HKESC-4, was established from a nude-mouse xenograft of a moderately differentiated esophageal squamous cell carcinoma (ESCC) developed from a 65-year-old Hong Kong Chinese man. The cellular characteristics (morphological, electron microscopic, and immunohistochemical studies), tumorigenicity in athymic nude mice, cytogenetic features, and DNA ploidy of the cell line were investigated. The cell line was maintained in vitro for 17 months and passaged 80 times. HKESC-4 grew as a monolayer, with a doubling time of 63 hours. The epithelial nature of HKESC-4 included the presence of cytokeratin intermediate filaments, as shown by antibodies (AE1/AF3, CAM5.2, and MAK 6), and the presence of the tonofilaments, as seen under electron microscopy. HKESC-4 was tumorigenic in nude mice and had DNA aneuploidy. The cytogenetic abnormalities of HKESC-4 included -1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -15, -16, -17, -18, -19, +20, -21, -22, +del(11)(p11), +i(11)(q10), and +21 marker chromosomes. Comparative genomic hybridization analysis demonstrated chromosomal gains at 1p36.13, 3q23 approximately q28, 5p15.33 approximately p15.1, 6p25.1 approximately p22.3, 7p21.3 approximately p11.2, 7q11.21 approximately q21.13, 8q23.3 approximately q23.3, 11p11.2, 11q12.1 approximately q13.2, 14q21.3 approximately q32.2, 17p13.3, 18p11.32 approximately p11.31, and 20p13 approximately p12.2 and chromosomal losses at 1q12, 2p25.1 approximately p24.3, 13p13 approximately p11.2, 21p, 22p13 approximately p11.2, and Y. The newly established cell line HKESC-4 promises to be a useful tool in future studies of molecular pathogenesis and therapeutics in ESCC.

PMID: 17889704 [PubMed - indexed for MEDLINE] 

Hepatocyte growth factor promotes cancer cell migration and angiogenic factors expression: a prognostic marker of human esophageal squamous cell carcinomas

Ren Y, Cao B, Law S, Xie Y, Lee PY, Cheung L, Chen Y, Huang X, Chan HM, Zhao P, Luk J, Vande Woude G, Wong J.

Abstract

PURPOSE:

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, play important roles in tumor development and progression. In this study, we measured the serum HGF levels in patients with esophageal squamous cell carcinoma (ESCC) to evaluate its relationships with clinicopathologic features and the role of HGF in ESCC.

EXPERIMENTAL DESIGN:

One hundred and forty-nine patients with ESCC were studied. Pretherapy serum was collected and ELISA was used to detect the concentrations of HGF, vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8). The function of HGF was shown by invasion chamber assay.

RESULTS:

Pretherapy serum HGF was found to be significantly higher in patients with ESCC than in control subjects. The levels of HGF correlated significantly with advanced tumor metastasis stage and survival. Multivariate analyses showed that serum HGF level in cell migration was an independent prognostic factor. Increased HGF serum levels correlated positively with serum levels of VEGF and IL-8. Our results also showed that HGF was overexpressed in ESCC tissues and cell lines. In vitro study showed that HGF could stimulate ESCC cell to express VEGF and IL-8 and markedly enhance invasion and migration of ESCC cells. Furthermore, HGF-induced IL-8 and VEGF expression was dependent on extracellular signal-regulated kinase signaling pathways. The inhibition of extracellular signal-regulated kinase activation reduced HGF-mediated IL-8 and VEGF expression.

CONCLUSIONS:

Our results suggest that serum HGF may be a useful biomarker of tumor progression and a valuable independent prognostic factor in patients with ESCC. HGF may be involved in the progression of ESCC as an autocrine/paracrine factor via enhancing angiogenesis and tumor cell invasion and migration.

PMID:16144920 [PubMed - indexed for MEDLINE] 

嬰幼兒成長 (iKid Magazine Volume 28)

引進固體食物 (iKid Magazine Volume 27)