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Ning J, Sala M, Reina J, Kalagiri R, Hunter T, McCullough BS. Histidine Phosphorylation: Protein Kinases and Phosphatases. Int J Mol Sci 2024; 25:7975. [PMID: 39063217 PMCID: PMC11277029 DOI: 10.3390/ijms25147975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/09/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Phosphohistidine (pHis) is a reversible protein post-translational modification (PTM) that is currently poorly understood. The P-N bond in pHis is heat and acid-sensitive, making it more challenging to study than the canonical phosphoamino acids pSer, pThr, and pTyr. As advancements in the development of tools to study pHis have been made, the roles of pHis in cells are slowly being revealed. To date, a handful of enzymes responsible for controlling this modification have been identified, including the histidine kinases NME1 and NME2, as well as the phosphohistidine phosphatases PHPT1, LHPP, and PGAM5. These tools have also identified the substrates of these enzymes, granting new insights into previously unknown regulatory mechanisms. Here, we discuss the cellular function of pHis and how it is regulated on known pHis-containing proteins, as well as cellular mechanisms that regulate the activity of the pHis kinases and phosphatases themselves. We further discuss the role of the pHis kinases and phosphatases as potential tumor promoters or suppressors. Finally, we give an overview of various tools and methods currently used to study pHis biology. Given their breadth of functions, unraveling the role of pHis in mammalian systems promises radical new insights into existing and unexplored areas of cell biology.
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Affiliation(s)
- Jia Ning
- Correspondence: (J.N.); (B.S.M.)
| | | | | | | | | | - Brandon S. McCullough
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; (M.S.); (J.R.); (R.K.); (T.H.)
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NDPKA is not just a metastasis suppressor - be aware of its metastasis-promoting role in neuroblastoma. J Transl Med 2018; 98:219-227. [PMID: 28991262 DOI: 10.1038/labinvest.2017.105] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/22/2017] [Accepted: 07/24/2017] [Indexed: 12/20/2022] Open
Abstract
NDPK-A, encoded by nm23-H1 (also known as NME1) was the first metastasis suppressor discovered. Much of the attention has been focused on the metastasis-suppressing role of NDPK-A in human tumors, including breast carcinoma and melanoma. However, compelling evidence points to a metastasis-promoting role of NDPK-A in certain tumors such as neuroblastoma and lymphoma. To balance attention on this contrariety of NDPK-A in different cancer types, this review addresses the metastasis-promoting role of NDPK-A in neuroblastoma. Neuroblastoma is an embryonic tumor, arising from neural crest cells that fail to differentiate into the sympathetic nervous system. We summarize and discuss nm23-H1 genetics and the prognosis of neuroblastoma, structural and functional changes associated with the S120G mutation of NDPK-A, as well as the evidence supporting the role of NDPK-A as a metastasis promoter. Also discussed are the NDPK-A relevant molecular determinants of neuroblastoma metastasis, and metastasis-relevant neural crest development. Because of NDPK-A's dichotomous role in tumor metastasis as both a suppressor and a promoter, tumor genome/exome profiles are necessary to identify the molecular drivers of metastasis in the NDPK-A network for developing tumor-specific therapies.
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Rasool RU, Nayak D, Chakraborty S, Jamwal VL, Mahajan V, Katoch A, Faheem MM, Iqra Z, Amin H, Gandhi SG, Goswami A. Differential regulation of NM23-H1 under hypoxic and serum starvation conditions in metastatic cancer cells and its implication in EMT. Eur J Cell Biol 2017; 96:164-171. [PMID: 28216015 DOI: 10.1016/j.ejcb.2017.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 12/04/2016] [Accepted: 01/26/2017] [Indexed: 01/15/2023] Open
Abstract
Multiple stresses are prevalent inside the tumor microenvironment rendering tumor growth, neighboring invasion and metastasis of the cancer cells to distant organs. NM23-H1 is the first metastasis suppressor gene identified and known to be implicated as an important regulator of stress-induced metastasis. Herein, we demonstrated that prototypical NM23-H1 expression diminished during hypoxia and serum starvation in Panc-1/MDA-MB-231 cells, but converse invasion patterns were obtained in these two diverse stresses. Supportingly, a compelling discrete difference in mRNA and protein levels of NM23-H1 was achieved in hypoxia as well as serum starvation. Knockdown of NM23-H1 activates EMT whereas the similar effects are subdued in serum starvation where NM23-H1 down-modulation prompted E-cadherin upregulation. Stable NM23-H1 expression augmented E-cadherin levels along with retardation in invadopodea formation and invasion. In hypoxia/serum starvation excess NM23-H1 effectively modulated the Twist1 promoter activity. Thus, differential regulation of NM23-H1 may corroborate/abrogate EMT depending on the nature of stress, tumor microenvironment and cellular context.
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Affiliation(s)
- Reyaz Ur Rasool
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Debasis Nayak
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Souneek Chakraborty
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Vijay Lakshmi Jamwal
- Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Vidushi Mahajan
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Archana Katoch
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Mir Mohd Faheem
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Zainab Iqra
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Hina Amin
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Sumit G Gandhi
- Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Anindya Goswami
- Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
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Kawai M, Komiyama H, Hosoya M, Okubo H, Fujii T, Yokoyama N, Sato C, Ueyama T, Okuzawa A, Goto M, Kojima Y, Takahashi M, Sugimoto K, Ishiyama S, Munakata S, Ogura D, Niwa SI, Tomiki Y, Ochiai T, Sakamoto K. Impact of chromosome 17q deletion in the primary lesion of colorectal cancer on liver metastasis. Oncol Lett 2016; 12:4773-4778. [PMID: 28101224 DOI: 10.3892/ol.2016.5271] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/01/2016] [Indexed: 01/15/2023] Open
Abstract
Colorectal cancer is a prevalent malignancy worldwide, and investigations are required to elucidate the underlying carcinogenic mechanisms. Amongst these mechanisms, de novo carcinogenesis and the adenoma to carcinoma sequence, are the most understood. Metastasis of colorectal cancer to the liver often results in fatality, therefore, it is important for any associated risk factors to be identified. Regarding the treatment of the disease, it is important to manage not only the primary colorectal tumor, but also the liver metastases. Previously, through gene variation analysis, chromosomal loss has been indicated to serve an important role in liver metastasis. Such analysis may aid in the prediction of liver metastasis risk, alongside individual responses to treatment, thus improving the management of colorectal cancer. In the present study, we aimed to clarify a cause of the liver metastasis of colorectal cancer using comparative genomic hybridization analysis. A total of 116 frozen samples were analyzed from patients with advanced colorectal cancer that underwent surgery from 2004 to 2011. The present study analyzed mutations within tumor suppressor genes non-metastatic gene 23 (NM23), deleted in colorectal carcinoma (DCC) and deleted in pancreatic carcinoma, locus 4 (DPC4), which are located on chromosomes 17 and 18 and have all been reported to affect liver metastasis of colorectal cancer. The association between chromosomal abnormalities (duplication and deletion) and liver metastasis of colorectal cancer was evaluated using comparative genomic hybridization. Cluster analysis indicated that the group of patients lacking the long arm of chromosome 17 demonstrated the highest rate of liver metastasis. No significant association was observed between the frequency of liver metastases for synchronous and heterochronous colorectal cancer cases and gene variation (P=0.206). However, when these liver metastasis cases were divided into the synchronous and heterochronous types, the ratio of each was significantly different between gene variation groups, classified by the existence of the 17q deletion (P=0.023). These results indicate that the deletion of 17q may act as a predictive marker of liver metastasis in postoperative states.
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Affiliation(s)
- Masaya Kawai
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Hiromitsu Komiyama
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Masaki Hosoya
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Haruna Okubo
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Tomoaki Fujii
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Norihiko Yokoyama
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Chiyo Sato
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Takae Ueyama
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Atsushi Okuzawa
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Michitoshi Goto
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Yutaka Kojima
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Makoto Takahashi
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kiichi Sugimoto
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Shun Ishiyama
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Shinya Munakata
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Dai Ogura
- Link Genomics Inc., Tokyo 103-0012, Japan
| | | | - Yuichi Tomiki
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Takumi Ochiai
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Evaluation of serum nucleoside diphosphate kinase A for the detection of colorectal cancer. Sci Rep 2016; 6:26703. [PMID: 27222072 PMCID: PMC4879623 DOI: 10.1038/srep26703] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 05/09/2016] [Indexed: 01/27/2023] Open
Abstract
We previously described the over-expression of nucleoside diphosphate kinase A (NDKA) in tumours and serum from colorectal cancer (CRC) patients, suggesting its use as biomarker. In this study we evaluated the diagnostic accuracy of serum NDKA to detect advanced neoplasia (CRC or advanced adenomas). Furthermore, the performance of NDKA was compared with the faecal immunochemical test (FIT). The study population included a case-control cohort and a screening cohort (511 asymptomatic first-degree relatives of CRC patients that underwent a colonoscopy and a FIT). Serum NDKA was elevated in CRC patients in the case-control cohort (p = 0.002). In the screening cohort, NDKA levels were higher for advanced adenomas (p = 0.010) and advanced neoplasia (p = 0.006) compared to no neoplasia. Moreover, elevated NDKA was associated with severe characteristics of adenomas (≥3 lesions, size ≥ 1 cm or villous component). Setting specificity to 85%, NDKA showed a sensitivity of 30.19% and 29.82% for advanced adenomas and advanced neoplasia, respectively. NDKA combined with FIT (100 ng/mL cut-off) detected advanced adenomas and advanced neoplasia with 45.28% and 49.12% sensitivity, with specificity close to 90%. The combination of serum NDKA and FIT can improve the detection of advanced neoplasia, mainly for lesions located on the proximal colon, in asymptomatic individuals with CRC family-risk.
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Sarris M, Konopka M, Soon Lee C. nm23 Expression in Adenocarcinomas of The Gastrointestinal Tract. J Histotechnol 2013. [DOI: 10.1179/his.2000.23.4.311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Chen WC, Lin MS, Zhang BF, Fang J, Zhou Q, Hu Y, Gao HJ. Survey of molecular profiling during human colon cancer development and progression by immunohistochemical staining on tissue microarray. World J Gastroenterol 2007; 13:699-708. [PMID: 17278192 PMCID: PMC4066002 DOI: 10.3748/wjg.v13.i5.699] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the molecular events taking place during human colon cancer development and progression through high-throughput tissue microarray analysis.
METHODS: We constructed two separate tissue microarrays containing 1.0 mm or 1.5 mm cylindrical samples acquired from 112 formalin-fixed and paraffin-embedded blocks, including carcinomas (n = 85), adenomatous polyps (n = 18), as well as normal para-cancerous colon tissues (n = 9). Immunohistochemical staining was applied to the analysis of the consecutive tissue microarray sections with antibodies for 11 different proteins, including p53, p21, bcl-2, bax, cyclin D1, PTEN, p-Akt1, β-catenin, c-myc, nm23-h1 and Cox-2.
RESULTS: The protein expressions of p53, bcl-2, bax, cyclin D1, β-catenin, c-myc, Cox-2 and nm23-h1 varied significantly among tissues from cancer, adenomatous polyps and normal colon mucosa (P = 0.003, P = 0.001, P = 0.000, P = 0.000, P = 0.034, P = 0.003, P = 0.002, and P = 0.007, respectively). Chi-square analysis showed that the statistically significant variables were p53, p21, bax, β-catenin, c-myc, PTEN, p-Akt1, Cox-2 and nm23-h1 for histological grade (P = 0.005, P = 0.013, P = 0.044, P = 0.000, P = 0.000, P = 0.029, P = 0.000, P = 0.008, and P = 0.000, respectively), β-catenin, c-myc and p-Akt1 for lymph node metastasis (P = 0.011, P = 0.005, and P = 0.032, respectively), β-catenin, c-myc, Cox-2 and nm23-h1 for distance metastasis (P = 0.020, P = 0.000, P = 0.026, and P = 0.008, respectively), and cyclin D1, β-catenin, c-myc, Cox-2 and nm23h1 for clinical stages (P = 0.038, P = 0.008, P = 0.000, P = 0.016, and P = 0.014, respectively).
CONCLUSION: Tissue microarray immunohistochemical staining enables high-throughput analysis of genetic alterations contributing to human colon cancer development and progression. Our results implicate the potential roles of p53, cyclin D1, bcl-2, bax, Cox-2, β-catenin and c-myc in development of human colon cancer and that of bcl-2, nm23-h1, PTEN and p-Akt1 in progression of human colon cancer.
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Affiliation(s)
- Wei-Chang Chen
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China.
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Abstract
Metastatic growth is a selective, non-random process, which in the case of colorectal cancer, frequently occurs in the liver and is the major cause of cancer related death in these patients. This review summarises attempts to find biological and molecular markers of metastasis and their role in establishment of secondary tumours. Recent evidence suggests that liver metastases are phenotypically different to the primary from which they were derived and thus represent a separate disease entity.
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Affiliation(s)
- Nigel C Bird
- Liver Research Group, Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield, United Kingdom.
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Elagoz S, Egilmez R, Koyuncu A, Muslehiddinoglu A, Arici S. The intratumoral microvessel density and expression of bFGF and nm23-H1 in colorectal cancer. Pathol Oncol Res 2006; 12:21-7. [PMID: 16554912 DOI: 10.1007/bf02893427] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2005] [Accepted: 11/20/2005] [Indexed: 11/28/2022]
Abstract
It has previously been reported that intratumoral microvessel density (IMD), and the expression of bFGF and nm23-H1 are useful prognostic markers in colorectal cancer (CRC). In this study, a total of 100 CRCs were evaluated histopathologically, and IMD, bFGF and nm23-H1 expression were assessed by immunohistochemistry. IMD of patients increased with grade and stage, and this increase was statistically significant (p<0.05). A significantly higher incidence of high bFGF expression scores was also associated with increasing grade and stage (p<0.05). However, there was no significant difference between the grades in nm23-H1 expression (p=0.234). nm23-H1 expression occurred with lower incidence in stages C1, C2 and D than in stages B1 and B2 (p<0.05). Thus, a negative correlation was found between nm23-H1 expression and stage or lymph node metastasis (LNM) (p<0.05). IMD and bFGF expression were positively correlated with grade, stage, LNM, and lymphovascular invasion. Although positive correlation was found between IMD and bFGF, nm23-H1 expression negatively correlated with both of them. As a result, in clinical practice, increased IMD and bFGF expression and decreased nm23-H1 expression may provide valuable information in characterizing the malignant phenotype.
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Affiliation(s)
- Sahande Elagoz
- Department of Pathology, Cumhuriyet University School of Medicine, Sivas, 58140, Turkey.
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Kapitanović S, Cacev T, Berković M, Popović-Hadzija M, Radosević S, Seiwerth S, Spaventi S, Pavelić K, Spaventi R. nm23-H1 expression and loss of heterozygosity in colon adenocarcinoma. J Clin Pathol 2005; 57:1312-8. [PMID: 15563674 PMCID: PMC1770523 DOI: 10.1136/jcp.2004.017954] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND The discovery that genetic alterations in oncogenes and tumour suppressor genes accompany tumour formation in many human tumours has encouraged the search for genes that promote or suppress tumour spread and metastasis; nm23 is a promising candidate for a metastasis suppressing gene. AIMS To evaluate whether expression of nm23-H1 protein or loss of heterozygosity (LOH) of the nm23-H1 gene is associated with colon cancer progression. MATERIALS/METHODS Paraffin wax embedded tissue sections were analysed immunohistochemically. DNA isolated from normal and tumour tissue was used for LOH analysis using a variable nucleotide tandem repeat (VNTR) marker located in the untranslated 5' region of the nm23-H1 gene. RNA isolated from tumour and normal tissue was used for "real time" RT-PCR. RESULTS Of 102 adenocarcinomas examined, 58.8% stained weakly for nm23-H1 protein. There was a negative correlation between nm23-H1 positivity and tumour histological grade. In VNTR analysis, 70.2% of patients were informative and 27.4% of tumours had nm23-H1 LOH. There was a positive correlation between nm23-H1 LOH and both tumour histological grade and Dukes's stage. Expression of nm23-H1 mRNA was increased in 22 of 30 colon tumours compared with normal tissue. No significant correlation was found between nm23-H1 mRNA expression and histological grade or Dukes's stage of tumours. CONCLUSIONS These findings suggest that nm23-H1 protein expression in early stages may have a role in suppressing metastasis in sporadic colon cancer, whereas at a later stage both reduced nm23-H1 protein expression and LOH of the nm23-H1 gene may play role in colon cancer progression and metastasis.
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Affiliation(s)
- S Kapitanović
- Division of Molecular Medicine, Rudjer Bosković Institute, HR-10000 Zagreb, Croatia.
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Kapitanović S, Cacev T, Radosević S, Spaventi S, Spaventi R, Pavelić K. APC gene loss of heterozygosity, mutations, E1317Q, and I1307K germ-line variants in sporadic colon cancer in Croatia. Exp Mol Pathol 2004; 77:193-200. [PMID: 15507235 DOI: 10.1016/j.yexmp.2004.06.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Indexed: 11/25/2022]
Abstract
Colorectal carcinomas are characterized by multiple genetic aberrations that occur during tumorigenesis. Several tumor suppressor genes associated with colorectal carcinoma have been identified: MCC, APC, p53, nm23-H1, DCC, DPC4. We examined 73 cases of sporadic human colon cancer and corresponding normal tissue samples to evaluate the loss of heterozygosity (LOH) at the APC gene loci. The purpose of this study was also to evaluate whether the LOH at the APC gene is associated with clinicopathological characteristics in sporadic colon cancer. We also investigated presence and the frequency of the most common APC gene mutations and APC E1317Q and I1307K germ-line variants in Croatian colorectal cancer patients. Five markers in all patients were found to be heterozygous and informative for LOH analysis. LOH at the APC locus was detected in 30.1% of tumors were examined. The majority of APC gene LOH was observed in Dukes' B (55.6%) and in the moderately differentiated tumors (42.9%). Only 1309 APC gene mutation was detected in our samples. In one tumor sample, a new sporadic mutation of the APC gene in codon 1374 was detected. APC E1317Q and I1307K germ-line variants were not detected in our population. But APC E1317Q sporadic mutation was found in one tumor sample.
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Affiliation(s)
- Sanja Kapitanović
- Division of Molecular Medicine, Ruder Bosković Institute, Zagreb, Croatia.
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Palacios F, Schweitzer JK, Boshans RL, D'Souza-Schorey C. ARF6-GTP recruits Nm23-H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat Cell Biol 2002; 4:929-36. [PMID: 12447393 DOI: 10.1038/ncb881] [Citation(s) in RCA: 263] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2002] [Revised: 08/20/2002] [Accepted: 09/24/2002] [Indexed: 01/15/2023]
Abstract
ARF6-regulated endocytosis of E-cadherin is essential during the disassembly of adherens junctions in epithelial cells. Here, we show that activation of ARF6 promotes clathrin-dependent internalization of E-cadherin and caveolae at the basolateral cell surface. Furthermore, we demonstrate that ARF6-GTP, a constitutively activate form of ARF6, interacts with and recruits Nm23-H1, a nucleoside diphosphate (NDP) kinase that provides a source of GTP for dynamin-dependent fission of coated vesicles during endocytosis. Finally, we show that ARF6-mediated recruitment of Nm-23-H1 to cell junctions is accompanied by a decrease in the cellular levels of Rac1-GTP, consistent with previous findings that Nm23-H1 down-regulates activation of Rac1. These studies provide a molecular basis for ARF6 function in polarized epithelia during adherens junction disassembly.
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Affiliation(s)
- Felipe Palacios
- Department of Biological Sciences and the Walther Cancer Institute, University of Notre Dame, Notre Dame, IN, USA
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13
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Dursun A, Akyürek N, Günel N, Yamaç D. Prognostic implication of nm23-H1 expression in colorectal carcinomas. Pathology 2002; 34:427-32. [PMID: 12408341 DOI: 10.1080/0031302021000009342] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
AIMS Expression of nm23 has been identified as a potential metastatic suppressor. In this study, nm23-H1 expression, clinicopathological parameters and influences on clinical outcomes were investigated in colorectal carcinoma patients. METHODS Immunostaining was performed on 185 colorectal carcinomas using a polyclonal anti-nm23-H1 antibody. RESULTS The nm23-H1 immunoreactivity was weak in 31 (17%), moderate in 48 (26%) and strong in 106 (57%) cases. The well differentiated adenocarcinomas showed significantly strong staining for nm23-H1 compared with the moderately and poorly differentiated adenocarcinomas (chi2 test, P<0.001). Advanced tumour stages were associated with reduced nm23-H1 expression (P<0.001). There was an inverse correlation with angiolymphatic invasion, nodal metastasis and liver metastasis (univariate logistic regression analysis, P<0.001). In univariate analysis, patients with reduced expression of nm23-H1 had significantly shorter overall and disease-free survival than the strong expression group (log-rank test for trend, P=0.002 and P=0.003, respectively). CONCLUSIONS Our results indicated that reduced nm23-H1 expression showed poor prognosis in colorectal carcinomas. As a result, nm23-H1 expression might be a useful marker to predict outcome while planning treatment.
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Affiliation(s)
- Ayşe Dursun
- Pathology Department, Gazi University Medical School, Ankara, Turkey.
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Günther K, Dworak O, Remke S, Pflüger R, Merkel S, Hohenberger W, Reymond MA. Prediction of distant metastases after curative surgery for rectal cancer. J Surg Res 2002; 103:68-78. [PMID: 11855920 DOI: 10.1006/jsre.2001.6312] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND This study was performed to define selection criteria for adjuvant therapy in rectal cancer. MATERIALS AND METHODS An immunohistochemical analysis using nine monoclonal antibodies against CEA, CD15s, CD44v6, DCC, E-cadherin, EGF-R, NM23, PAI-1, and P53 was performed on paraffin sections of two matched (age, gender, UICC stage [I-III], year of operation [1982-1991]) groups of patients (n = 2 x 64) with rectal carcinoma curatively treated by surgery alone. The two groups differed only with regard to metachronous distant metastatic spread. In order to exclude the influence of surgery, all patients had to meet the selection criterion "free of locoregional disease." Follow-up was prospective (median 80 months). Conventional staining procedures and immunohistochemical evaluation were used. Tumor grading and lymphatic and extramural venous invasion were also investigated. Analysis was performed with Fisher's exact test and Kaplan-Meier estimates of disease-free survival (log rank). The Cox model was used for multivariate analysis. RESULTS In univariate analysis only grading (P < 0.001) and extramural venous invasion (P < 0.001) correlated significantly with metachronous metastases. In multivariate analysis, beside grading (P = 0.010) and extramural venous invasion (P = 0.011), CD15s (P = 0.042) was also of significance. All other immunohistochemical markers failed. CONCLUSIONS The histopathological parameters grading and extramural venous invasion appear to be acceptable predictors of metachronous distant spread in curatively resected rectal cancer. In contrast to the immunohistochemical markers, grading seems to better reflect the individual tumor phenotype and its behavior.
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Affiliation(s)
- Klaus Günther
- Department of Surgery, Biometry and Epidemiology of the University of Erlangen, Erlangen, D-91054 Germany
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15
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Sanz L, Gonzáleza JJ, Martínez E, Fresno MF. Relación de nm23-H1 con las metástasis en el cáncer de recto. Cir Esp 2002. [DOI: 10.1016/s0009-739x(02)72040-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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16
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Friess H, Guo XZ, Tempia-Caliera AA, Fukuda A, Martignoni ME, Zimmermann A, Korc M, Büchler MW. Differential expression of metastasis-associated genes in papilla of vater and pancreatic cancer correlates with disease stage. J Clin Oncol 2001; 19:2422-32. [PMID: 11331321 DOI: 10.1200/jco.2001.19.9.2422] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
PURPOSE Papilla of Vater cancer has a much better prognosis than pancreatic cancer. It is not known whether this is the result of differences in the tumor biology of the two malignancies. Because metastasis formation is a critical step in tumor progression and a negative prognostic factor, we compared the expression of nm23-H1 and KAI1, two metastasis-suppressing genes, in papilla of Vater cancer and pancreatic cancer. PATIENTS AND METHODS Analysis was performed in nine normal human papilla of Vater samples, 27 papilla of Vater cancers, 16 normal pancreatic samples, and 29 pancreatic cancers. Expression of nm23-H1 and KAI1 was analyzed by Northern blot analysis and in situ hybridization. In addition, immunohistochemistry was performed to localize the respective proteins. RESULTS There was no difference in nm23-H1 and KAI1 mRNA expression levels in normal versus cancerous papilla of Vater samples. In contrast, nm23-H1 and KAI1 RNA expression was upregulated in early tumor stages of pancreatic cancer and reduced in advanced tumor stages. When expression of nm23-H1 and KAI1 RNA was analyzed by use of in situ hybridization, normal epithelial cells of the papilla of Vater exhibited mRNA staining intensity similar to that of papilla of Vater cancer cells. Similar levels of nm23-H1 and KAI1 immunoreactivity also were observed in these samples. In contrast, early stage pancreatic cancer samples exhibited stronger nm23-H1 and KAI1 immunoreactivity than normal controls. Furthermore, early pancreatic cancer stages exhibited higher KAI1 and nm23-H1 immunostaining than advanced tumor stages. CONCLUSION Differences in the expression patterns of the two tumor suppressor genes nm23-H1 and KAI1 may contribute to the different prognoses of papilla of Vater cancer and pancreatic cancer. Our findings support the hypothesis that biologic differences rather than earlier diagnosis influence the different outcomes of these two tumor entities.
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Affiliation(s)
- H Friess
- Department of Visceral and Transplantation Surgery and Institute of Pathology, University of Bern, Inselspital, Bern, Switzerland.
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17
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Sugai T, Habano W, Nakamura S, Yoshida T, Uesugi N, Sasou S, Itoh C, Katoh R. Use of crypt isolation to determine loss of heterozygosity of multiple tumor suppressor genes in colorectal carcinoma. Pathol Res Pract 2000; 196:145-50. [PMID: 10729918 DOI: 10.1016/s0344-0338(00)80094-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Analysis of loss of heterozygosity (LOH) is very important in the study of tumor suppressor genes. However, accurate LOH analysis of tumor suppressor genes is difficult because of dilution by contaminating non-tumor DNA. Thus, enrichment of tumor DNA is required to accurately determine LOH of the tumor. We developed a new application of the fluorescent polymerase chain reaction by coupling it with crypt isolation to accurately assess the incidence of LOH of tumor suppressor genes in 45 colorectal carcinomas. LOH was observed at p53 in 26 of 37 tumors (70.3%), at APC in 13 of 35 (37.1%), at DCC in 16 of 25 (64.0%), at NF-2 in 5 of 23 (21.7%), and at nm23 H-1 in 7 of 30 (23.3%). We could clearly determine LOH of these genes because the crypt isolation technique was used. Although the incidence of LOH at each of these loci, as determined by using this technique, was similar to that obtained in previous studies using conventional methods, this method provides a simpler, more accurate way to assess LOH. In addition, the morphology of the samples can be analyzed before genetic analysis.
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Affiliation(s)
- T Sugai
- Division of Pathology, Iwate Medical University Morioka, Japan
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18
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Yoo CH, Noh SH, Kim H, Lee HY, Min JS. Prognostic significance of CD44 and nm23 expression in patients with stage II and stage IIIA gastric carcinoma. J Surg Oncol 1999; 71:22-8. [PMID: 10362087 DOI: 10.1002/(sici)1096-9098(199905)71:1<22::aid-jso5>3.0.co;2-i] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND AND OBJECTIVES Predicting the prognosis in gastric carcinoma patients with intermediate stages is difficult. We investigated the prognostic impacts of CD44 and nm23 expression in a homogeneous group of patients with stage II and IIIA gastric carcinoma who had undergone curative resections. METHODS A total of 261 paraffin-embedded gastric carcinomas were stained with the monoclonal antibodies CD44 and nm23 using the labeled streptovidin biotin method. RESULTS The expression of CD44 and nm23 was detected, respectively, in 31.0% (81/261) and 70.1% (183/261) of all tumors. There was no correlation between CD44 expression and clinicopathological variables. However, nm23 was more frequently expressed in older patients with differentiated adenocarcinoma. A significant difference in 5-year survival rates was found between patients with CD44-positive (43.2%) and CD44-negative tumors (63.4%), (P = 0.0018). However, there was no significant difference in 5-year survival rates between patients with nm23-positive (54.7%) and nm23-negative tumors (62.7%) (P = 0.2734). CONCLUSIONS CD44 expression was a significant adverse prognostic factor in gastric carcinoma and may be a predictor of metastatic potential of the primary tumor. By contrast, immunohistochemical detection of nm23 expression was not a predictor of outcome of patients with gastric carcinoma.
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Affiliation(s)
- C H Yoo
- Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea
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19
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Tabuchi Y, Nakamura T, Kuniyasu T, Ohno M, Nakae S. Expression of nm23-H1 in colorectal cancer: no association with metastases, histological stage, or survival. Surg Today 1999; 29:116-20. [PMID: 10030735 DOI: 10.1007/bf02482235] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The correlations of nm23-H1 expression in primary cancer lesions with the already confirmed 14 prognostic variables and survival were examined in 52 advanced colorectal cancer patients, because the clinical roles of nm23-H1 expression in the cancer lesions remain controversial. An immunohistochemical expression of nm23-H1 was found in 23 lesions (positive group) but not found in 29 lesions (negative group). No significant difference between the positive and negative groups was found according to 12 clinicopathological variables including vascular invasion, lymph node and liver metastases, and histological stage. The carcinoembryonic antigen levels (21.5+/-33.4 ng/ml) of the draining venous blood and argyrophilic nucleolar organizer regions score (3.35+/-1.36 per nucleus) of the cancer cells in the positive group were not significantly diffeent from those (34.1+/-102.9 ng/ml and 3.32+/-1.00 per nucleus, respectively) in the negative group. In addition, no significant difference was found in the survival curves or the 5-year survival rates of the positive and negative groups. From these results, it may be concluded that the nm23-H1 expression was not associated with the aforementioned prognostic variables and the prognosis of advanced colorectal cancer patients.
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Affiliation(s)
- Y Tabuchi
- Faculty of Health Science, Kobe University School of Medicine, Japan
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20
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Abstract
BACKGROUND Expression of nm23 has been shown to be inversely correlated with the metastatic potential of several human cancers. In the current study, the expression and prognostic impact of nm23 was immunohistochemically studied in 413 curatively resected gastric carcinomas. METHODS Tumor sections of the 413 gastric carcinomas were stained with a polyclonal antibody that was raised against the nm23-H1/NDP kinase A, which is identical to the nm23-H1 gene product. RESULTS Expression of nm23 was detected in 84.5% (n = 349) of all tumors, in the majority of cases (71.2%) causing a homogeneous staining reaction in more than 75% of tumor cells. Expression of nm23 was positively correlated with the intestinal type of tumor, according to the Lauren classification and advanced pT categories, and was also correlated with the presence of blood and lymphatic vessel invasion. In contrast, no correlation could be demonstrated between nm23 expression and lymph node involvement. As shown in univariate analysis, patients with nm23 positive tumors, especially those with nm23 positive diffuse-type carcinomas, had significantly shorter overall survival than patients with nm23 negative tumors (P = 0.03 and P = 0.0065, respectively). However, in a multivariate analysis that included the prognostic parameters pT category, pN category, and blood and lymphatic vessel invasion, this prognostic impact was not maintained. CONCLUSIONS In contrast to results for breast and colorectal carcinomas, our results for 413 gastric carcinomas showed that expression of the designated metastasis suppressor gene nm23 is correlated with aggressive tumor growth and poor prognosis but is not an independent prognostic marker.
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Affiliation(s)
- W Müller
- Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany
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21
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Zeng ZS, Guillem JG. Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer. Br J Cancer 1998; 78:349-53. [PMID: 9703281 PMCID: PMC2063024 DOI: 10.1038/bjc.1998.497] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Experimental in vitro and animal data support an important role for matrix metalloproteinases (MMPs) in cancer invasion and metastasis via proteolytic degradation of the extracellular matrix (ECM). Our previous data have shown that MMP-9 mRNA is localized to the interface between liver metastasis and normal liver tissue, indicating that MMP-9 may play an important role in liver metastasis formation. In the present study, we analysed the cellular enzymatic expression of MMP-9 in 18 human colorectal cancer (CRC) liver metastasis specimens by enzyme-linked immunosorbent assay (ELISA) and zymography. ELISA analysis reveals that the latent form of MMP-9 is present in both liver metastasis and paired adjacent normal liver tissue. The mean level of the latent form of MMP-9 is 580+/-270 ng per mg total tissue protein (mean+/-s.e.) in liver metastasis vs 220+/-90 in normal liver tissue. However, this difference is not significantly different (P = 0.26). Using gelatin zymography, the 92-kDa band representative of the latent form is present in both liver metastasis and normal liver tissue. However, the 82 kDa band, representative of the active form of MMP-9, was seen only in liver metastasis. This was confirmed by Western blot analysis. Our observation of the unique presence of the active form of MMP-9 within liver metastasis suggests that proMMP-9 activation may be a pivotal event during CRC liver metastasis formation.
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Affiliation(s)
- Z S Zeng
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
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22
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Nakamura T, Tabuchi Y, Ohno M. Relations of nm23 expression to clinicopathologic variables and proliferative activity of gastric cancer lesions. CANCER DETECTION AND PREVENTION 1998; 22:246-50. [PMID: 9618047 DOI: 10.1046/j.1525-1500.1998.0oa27.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Relationships of nm23 expression and 12 clinicopathologic variables and proliferative activity of cancer cells were examined in 55 gastric cancer patients to clarify the effects of nm23 expression on the factors and activity in gastric cancer. Expression of nm23 was determined by immunohistochemically stained sections using a monoclonal antibody, nm23H-1. Proliferative activity was immunohistochemically evaluated by proliferating cell nuclear antigen (PCNA) labeling index (LI) using a monoclonal antibody PC10. Expression of nm23 was found in 24 lesions (positive group) but not in 31 lesions (negative group). With regard to clinicopathologic variables, a significant (p < 0.05) difference between the positive and negative groups was found in 1 of the 12 factors, depth of cancer invasion. PCNA LI (48.9 +/- 11.6%) of the former group was significantly (p < 0.05) higher than that (40.3 +/- 12.6%) ot the latter, although multiple regression analysis showed that nm23 expression was not one of the most influencing variables for PCNA LI. The results may suggest that expression of nm23 in gastric cancer lesions is correlated to tumor progression and/or proliferation rather than suppression of metastasis.
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Affiliation(s)
- T Nakamura
- First Department of Surgery, Kobe University School of Medicine, Japan
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23
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Cheah PY, Cao X, Eu KW, Seow-Choen F. NM23-H1 immunostaining is inversely associated with tumour staging but not overall survival or disease recurrence in colorectal carcinomas. Br J Cancer 1998; 77:1164-8. [PMID: 9569056 PMCID: PMC2150137 DOI: 10.1038/bjc.1998.193] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The NM23-H1 gene product has been recently identified as a potential metastasis suppressor. Studies on breast carcinomas have shown an inverse correlation between NM23-H1 status and stage of carcinogenesis and overall survival. However, in colorectal cancer, conflicting data have been reported. This study aimed to investigate whether NM23-H1 immunostaining is correlated with tumour stage, overall survival, disease recurrence, tumour differentiation, age and sex in colorectal carcinomas for the Singapore population using chi-square analysis. The staining was performed on 141 paraffin-embedded surgical specimens collected between 1991 and 1992 using a monoclonal anti-NM23-H1 antibody. Follow-up of patients was until time of death or for 5 years. There was a very significant inverse association between tumour staging and NM23-H1 status (P = 0.0004). However, NM23-H1 expression was not significantly correlated to overall 5-year survival, disease recurrence, tumour differentiation, age or sex. Thus, although NM23-H1 may be involved in suppressing metastasis, NM23-H1 immunohistochemistry has no prognostic value in colorectal cancer. This is the first report of a significant inverse association of NM23-H1 status with tumour staging in colorectal cancer which showed no correlation with overall survival or disease recurrence. Our result thus cautions against the practice of equating an inverse relation of genetic markers with tumour staging to survival or disease recurrence.
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Affiliation(s)
- P Y Cheah
- Department of Colorectal Surgery, Singapore General Hospital, Republic of Singapore
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24
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Bertheau P, Steinberg SM, Merino MJ. C-erbB-2, p53, and nm23 gene product expression in breast cancer in young women: immunohistochemical analysis and clinicopathologic correlation. Hum Pathol 1998; 29:323-9. [PMID: 9563780 DOI: 10.1016/s0046-8177(98)90111-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We studied c-erbB-2, p53, and nm23 gene products in 112 primary breast carcinomas. Fifty patients were aged 35 years or younger, and 62 were aged 36 to 50. Clinicopathological criteria including clinical stage, hormone receptor status, histological types, histological grades, and lymph node status, were reviewed. Disease-free survival (DFS) and overall survival (OS) were analyzed. Immunohistochemical findings were assessed semiquantitatively. Correlation between clinicopathological criteria, survival data, and immunohistochemical findings have been made. Patients aged younger than 35 years with stage I to II disease had a shorter DFS (P = .03) than older patients. However, no other clinicopathological finding was associated with age. Neither was there association between age and c-erbB-2, p53, or nm23 patterns of expression. p53 positivity was associated with high histological grade (P = .003) and with progesterone receptor negativity (P = .045). Nm23 nuclear positivity was associated with early clinical stages (P = .011) and with absence of axillary lymph node metastasis (P = .007). p53 and c-erbB-2 overexpression were associated with shorter OS while nm23 nuclear positivity was associated with longer OS in univariate and multivariate analyses. Univariate analyses showed that c-erbB-2 or nm23 were potentially important prognostic factors in women aged 35 years or younger while p53 was associated with prognosis in women aged 36 to 50. Cox model analysis indicated that c-erbB-2 alone was associated with prognosis in women 35 years and younger, whereas p53 alone was associated with prognosis in 36- to 50-year-old women. These results suggest that breast cancer in the youngest women has some biological specificity.
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Affiliation(s)
- P Bertheau
- Laboratory of Surgical Pathology, Saint Louis Hospital, Paris, France
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25
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Kanitakis J, Euvrard S, Bourchany D, Faure M, Claudy A. Expression of the nm23 metastasis-suppressor gene product in skin tumors. J Cutan Pathol 1997; 24:151-6. [PMID: 9085150 DOI: 10.1111/j.1600-0560.1997.tb01569.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Nm23 is a gene with a putative metastasis-suppressor function, whose expression is inversely correlated with the metastatic potential of some solid malignancies. Because very few data exist concerning the role of nm23 in skin tumors, we studied the immunohistochemical expression of nm23 gene product in frozen sections of normal skin and of 104 cutaneous benign or malignant, epithelial and mesenchymal tumors. Nm23 was found expressed within basal cells of the epidermis and its appendages. All basal cell carcinomas showed diffuse immunoreactivity predominating within cells located at the periphery of tumor masses; in contrast, most squamous cell carcinomas, premalignant lesions and the benign epithelial lesions studied showed very weak, if any, immunoreactivity. Benign nevi and most malignant melanomas expressed nm23 immunoreactivity and the pattern observed was similar between primary and metastatic lesions. These results show that nm23 is differentially expressed in cutaneous tumors. It seems likely that the strong immunoreactivity of basal cell carcinomas, contrasting with the almost non-expression in squamous cell carcinomas, reflects the different metastatic potential of these two types of tumors. In melanomas, no direct correlation between the metastatic phenotype and nm23 expression could be detected. Our results suggest that the nm23 gene is involved in cutaneous carcinogenesis; its precise role deserves further study.
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MESH Headings
- Antigens, Neoplasm/biosynthesis
- Antigens, Neoplasm/genetics
- Biomarkers, Tumor/genetics
- Carcinoma, Basal Cell/genetics
- Carcinoma, Basal Cell/pathology
- Carcinoma, Basal Cell/secondary
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/secondary
- Genes, Tumor Suppressor
- Humans
- Immunohistochemistry
- Melanoma/genetics
- Melanoma/pathology
- Melanoma/secondary
- Monomeric GTP-Binding Proteins
- NM23 Nucleoside Diphosphate Kinases
- Nevus/genetics
- Nevus/pathology
- Nucleoside-Diphosphate Kinase
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Skin Neoplasms/secondary
- Transcription Factors/biosynthesis
- Transcription Factors/chemistry
- Transcription Factors/genetics
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Affiliation(s)
- J Kanitakis
- Department of Dermatology, Hôpital Ed. Herriot, Lyon, France
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26
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Cohn KH, Ornstein DL, Wang F, LaPaix FD, Phipps K, Edelsberg C, Zuna R, Mott LA, Dunn JL. The significance of allelic deletions and aneuploidy in colorectal carcinoma. Cancer 1997. [DOI: 10.1002/(sici)1097-0142(19970115)79:2<233::aid-cncr6>3.0.co;2-l] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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27
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Aryee DN, Simonitsch I, Mosberger I, Kos K, Mann G, Schlögl E, Pötschger U, Gadner H, Radaszkiewicz T, Kovar H. Variability of nm23-H1/NDPK-A expression in human lymphomas and its relation to tumour aggressiveness. Br J Cancer 1996; 74:1693-8. [PMID: 8956779 PMCID: PMC2077220 DOI: 10.1038/bjc.1996.616] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The nm23-H1 gene is a putative metastasis-suppressor gene encoding a 17 kDa protein with nucleoside diphosphate kinase activity. Expression of nm23-H1/NDPK-A correlates inversely with the metastasising potential of some human tumours and experimental animal cells. No nm23 expression studies exist for human malignant lymphomas so far. In this study, we examined nm23-H1 expression by Northern and immunohistochemical analysis in 106 primary lymphoma samples from patients with Hodgkin's disease (HD) (n = 15), high-grade non-Hodgkin's lymphoma (NHL) from different lineages (n = 71) and low-grade NHL (n = 20). Both inter- and intra-subtype variations in nm23-H1/NDPK-A expression levels were demonstrated by all disease subtypes. Besides this heterogeneity, a general trend towards highly malignant samples expressing higher nm23-H1/NDPK-A, levels than the low-grade lymphomas was observed. Both adult and childhood HD and high-grade NHL samples exhibited significantly higher NDPK-A expression than the low-grade NHL found only in adults. High nm23-H1/NDPK-A levels in lymphoma samples did not always reflect proliferative activity of tumour cells as monitored by Ki-67 antigen staining. Fifty samples were further investigated for possible mutations in the nm23-H1 coding sequence by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and single-strand conformation polymorphism (SSCP) analysis. No mutation was found by this screening. Our results suggest a role for nm23-H1 expression in the disease aggressiveness of lymphomas.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Neoplasm/immunology
- Child
- Child, Preschool
- DNA Mutational Analysis
- Female
- Genes, Tumor Suppressor
- Hodgkin Disease/genetics
- Hodgkin Disease/immunology
- Hodgkin Disease/metabolism
- Hodgkin Disease/pathology
- Humans
- Infant
- Lymphoma, Non-Hodgkin/genetics
- Lymphoma, Non-Hodgkin/immunology
- Lymphoma, Non-Hodgkin/metabolism
- Lymphoma, Non-Hodgkin/pathology
- Male
- Middle Aged
- Monomeric GTP-Binding Proteins
- NM23 Nucleoside Diphosphate Kinases
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Nucleoside-Diphosphate Kinase
- Polymerase Chain Reaction/methods
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism
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Affiliation(s)
- D N Aryee
- Children's Cancer Research Institute, St Anna Kinderspital, Vienna, Austria
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28
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Lindmark G. NM-23 H1 immunohistochemistry is not useful as predictor of metastatic potential of colorectal cancer. Br J Cancer 1996; 74:1413-8. [PMID: 8912537 PMCID: PMC2074791 DOI: 10.1038/bjc.1996.557] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
This study aimed to investigate whether immunohistochemical staining for nm23-H1 protein in the primary tumour is correlated with tumour stage, tumour differentiation, DNA ploidy, cell proliferative index, p53 status and patient survival time in colorectal cancer. Full-cross colorectal cancer biopsies were collected from 202 consecutive surgical specimens between 1987 and 1990. Immunohistochemical expression of nm23-H1 protein was investigated in cryosections, using a monoclonal anti-nm23-H1 antibody (clone NM 301). The staining pattern was classified as follows: strong homogeneous intensity, moderate homogeneous intensity, moderate focal intensity, or as negative. Immunohistochemical expression of p53 was investigated using a monoclonal anti-p53 antibody (DO-7). The DNA ploidy and cell proliferative index were determined by flow cytometry. Possible correlation between nm23-H1 staining patterns and the other studied tumour characteristics was explored at the end of 1994. Median survival time of living patients was 66 months, range 50-93 months. No correlation was found between various nm23-H1 staining patterns and tumour stage, cell proliferative index or p53 status. Nm23-H1-negative tumours and tumours with moderate focal staining intensity were less differentiated than tumours with strong homogeneous or moderate homogeneous staining intensity (P < 0.05). Of the nm23-H1-negative tumours, a significantly higher number was near-diploid rather than aneuploid, as compared with those expressing positive nm23-H1 (P < 0.05). The number of dead patients in Dukes' stages B and C did not correlate significantly with the nm23-H1 staining pattern. The nm23-H1 staining pattern alone, or combined with either of the other explored tumour characteristics, did not correlate with patient survival time. Immunohistochemical studies of the nm23-H1 protein expression are of minor value in the staging and prognostic prediction of colorectal cancer.
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Affiliation(s)
- G Lindmark
- Department of Medical and Physiological Chemistry, University of Uppsala, Sweden
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29
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Zeng ZS, Guillem JG. Colocalisation of matrix metalloproteinase-9-mRNA and protein in human colorectal cancer stromal cells. Br J Cancer 1996; 74:1161-7. [PMID: 8883399 PMCID: PMC2075925 DOI: 10.1038/bjc.1996.511] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The matrix metalloproteinases (MMPs) are perceived as essential for tumour invasion and metastases. The purpose of this study was to determine the expression and cellular localisation of the 92 kDa type IV collagenase (MMP-9) protein and mRNA in human colorectal cancer (CRC). In CRC and matched normal mucosa specimens from 26 CRC patients, Northern blot hybridisation and Western blot analyses provide convincing evidence that MMP-9 is expressed in greater quantities in CRC than in normal tissue. The MMP-9 tumour to normal mucosa fold-increase (T/N) was 9.7 +/- 7.1 (mean +/- s.d.) (P < 0.001) for RNA and 7.1 +/- 3.9 (P < 0.001) for protein. The sites of MMP-9 mRNA and protein synthesis were colocalised in tumour stroma by in situ hybridisation and immunohistochemistry in 26 CRC samples. Both MMP-9 mRNA and protein signals were strongest in the population of stromal cells concentrated at the tumour-stroma interface of an invading tumour. Furthermore, MMP-9-positive cells were identified as macrophages using an antimacrophage antibody (KP1) in serial sections from ten CRC samples. Given the persistent localisation of MMP-9-producing macrophages to the interphase between CRC and surrounding stroma, our observations suggest that MMP-9 production is controlled, in part, by tumour-stroma cell interactions. Further studies are needed to determine the in vivo regulation of MMP-9 production from infiltrating peritumour macrophages.
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Affiliation(s)
- Z S Zeng
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA
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Holm R, Tanum G. Evaluation of the prognostic significance of nm23/NDP kinase and cathepsin D in anal carcinomas. An immunohistochemical study. Virchows Arch 1996; 428:85-9. [PMID: 8925129 DOI: 10.1007/bf00193935] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Reduced expression of nm23/NDP kinase and increased expression of cathepsin D seem to be correlated with a high metastatic potential for a variety of malignancies. Nm23/NDP kinase and cathepsin D have been correlated with several clinical variables, including survival in 96 patients with squamous cell carcinoma of the anal canal. Immunohistochemical methods were used on paraffin-embedded biopsies. Seventy-six (79%) anal carcinomas were nm23/NDP kinase positive, whereas 35 (36%) and 28 (29%) of the cases were cathepsin D positive in tumor cells and stromal cells, respectively. We have found no indication that the extent of cathepsin D staining has any prognostic significance. The overall survival of patients with tumours positive for nm23/NDP kinase in the cytoplasm was significantly shorter than that of patients with anal carcinomas negative for nm23/NDP kinase.
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Affiliation(s)
- R Holm
- Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway
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Zeng ZS, Guillem JG. Distinct pattern of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 mRNA expression in human colorectal cancer and liver metastases. Br J Cancer 1995; 72:575-82. [PMID: 7669564 PMCID: PMC2033901 DOI: 10.1038/bjc.1995.376] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are perceived as essential for tumour invasion and metastasis. In the present study, we compare the topographical pattern of MMP-9 and TIMP-1 expression in colorectal cancer and liver metastasis by in situ hybridisation. TIMP-1 mRNA was detected in all 26 colorectal cancers examined, while only 18 out of 26 (69.2%) were positive for MMP-9. Both MMP-9 and TIMP-1 mRNA were observed in all ten liver metastases but were absent in three adenomas and in all normal colonic mucosa and liver. There was no association between MMP-9 or TIMP-1 mRNA expression and degree of differentiation or size of Tumours. MMP-9 and TIMP-1 mRNA were similarly observed in the peritumour stroma cells rather than in tumour cells themselves. MMP-9 mRNA positive cells were round and identified as macrophages by immunostaining with an anti-macrophage antibody (KP1), while TIMP-1, mRNA was detected in spindle-shaped stromal cells. In liver metastases, MMP-9 localised within peritumour stroma or at the interface between the tumour stroma and normal liver, whereas TIMP-1 mRNA was located throughout the malignant tumour stroma. Our data demonstrate a distinct pattern of MMP-9 and TIMP-1 mRNA expression in colorectal cancer and liver metastases suggesting distinct cellular origins as well as separate patterns of regulation.
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Affiliation(s)
- Z S Zeng
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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MacDonald NJ, de la Rosa A, Steeg PS. The potential roles of nm23 in cancer metastasis and cellular differentiation. Eur J Cancer 1995; 31A:1096-100. [PMID: 7576999 DOI: 10.1016/0959-8049(95)00152-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The majority of cancer patients succumb to the consequences of metastatic disease. A correlation of increased nm23 expression to low metastatic potential has been established in several malignancies, based on published prognostic studies with tumour cohorts and transfection studies. Transfection of highly metastatic MDA-MB-435 human breast carcinoma cells with nm23-H1 cDNA resulted in a significant reduction in the metastatic potential in vivo. These transfections also showed inhibition of colonisation and motility, as well as morphological and biosynthetic differentiation in vitro. The biochemical mechanism of Nm23-H1 action, as well as the identity of proteins involved in its functional biochemical pathway, are still unknown. We summarise published and recent research concerning the role of the nm23 gene in metastasis and normal cellular differentiation.
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Affiliation(s)
- N J MacDonald
- Women's Cancers Section, National Cancer Institute, Bethesda, Maryland 20892-1500, USA
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