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Institute of Molecular and Cell Biology, Singapore 117609, Singapore [Q. Z., J-M. D., K. G., J. L., H-X. T., V. K., E. M., W. H.]; Department of Pediatrics, University of British Columbia, BC Research Institute for Children’s and Women’s Health, Vancouver, British Columbia V5Z 4H4, Canada [C. J. P.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Many genes have been implicated in the development and progression of colorectal cancer (4 , 5) . However, the identification of consistent genetic alterations associated with the transition from the primary tumors to metastatic colorectal liver disease has proved elusive. Gene expression profiling revealed recently that among 144 up-regulated genes detected in metastatic colorectal liver samples, PRL-3 is the only gene consistently overexpressed in all 18 of the cancer metastases examined, with essentially undetectable PRL-3 expression in normal colorectal epithelia and intermediate expression in advanced primary cancers (6) . The overexpression of the PRL-3 transcript is because of gene amplification in 3 of 12 metastases examined, whereas enhanced transcriptional activity likely accounts for elevated PRL-3 transcripts in the other metastases. This study suggests the possibility that an excess of PRL-3 phosphatase is a key alteration contributing to the acquisition of metastatic properties of the tumor cells, but cell biological and mechanistic evidence supporting such a role is lacking. In this study we provide evidence to support a causal role of PRL-3 and -1 in tumor metastasis.
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Materials and Methods |
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Generation of CHO Cells Stably Expressing EGFP-PRL-3 and EGFP-PRL-3 (C104S).
Synthetic oligonucleotides were purchased from Oligos Etc. (Wilsonville, OR). The Pyrococcus furiosus DNA polymerase was from Stratagene (La Jolla, CA). The pEGFP-C1 vector was from (Clontech).5
To prepare a plasmid (pEGFP-PRL-3) for expression of PRL-3 NH2-terminally tagged with EGFP (EGFP-PRL-3), forward primer 1 (5'-gtg aat tct atg gcc cgc atg aac cgg-3'), and reverse primer F (above) were used to retrieve the PRL-3 coding region by PCR. The PCR reaction was resolved by agarose gel electrophoresis, and the specific fragment (530 bp) was eluted and purified. The fragment was digested with EcoRI and BamHI, and then inserted into the corresponding sites of the pEGFP-C1 vector. To construct pEGFP-PRL-3 (C104S) containing an inactivating mutation of the essential catalytic cysteine residue to serine at position 104 in the phosphatase active site, forward primer 1 in combination with reverse primer 3 incorporating the desired nucleotide (C to G, italicized) substitution (5'-cag gcc cgc cac aga gtg cac aag-3') were used to retrieve the coding region for the NH2-terminal portion of PRL-3 (N-fragment). Forward primer 4 incorporating the desired nucleotide (G to C, italicized) substitution (5'-ctt gtg cac tct gtg gcg ggc ctg-3') and reverse primer F (above) were used to retrieve the coding region for the COOH-terminal portion of PRL-3 (C-fragment). The gel-purified N-fragment and C-fragment were mixed and used in a PCR reaction with forward primer 1 and reverse primer F to generate the entire cDNA encoding the mutant PRL-3 (C104S). After digestion with EcoRI and BamHI, the specific fragment (530 bp) was purified and cloned into the corresponding sites of pEGFP-C1 vector. The two expression constructs were confirmed by DNA sequencing and transfected into CHO-K1 (ATCC CCL-61) cells using Lipofectamine 2000 (Invitrogen). The cells were cultured in RPMI 1640 supplemented with 10% FBS and selected in 1 mg/ml of neomycin for 20–30 days to establish stable cell pools.
Cell Motility Assay.
This was performed as described (8)
using Transwells (6.5 mM diameter; 8 µM pore size polycarbonate membrane) obtained from Corning.6
Cells (1 x 105) in 0.5 ml serum-free medium were placed in the upper chamber, whereas the lower chamber was loaded with 0.8 ml medium containing 10% FBS. The total number of cells that migrated into the lower chamber was counted after 24 h of incubation at 37°C with 5% CO2.
Cell Invasion Assay.
This was carried out essentially as described (8
, 9)
. Transwells (BD Biocoat Matrigel 24-well invasion chamber) with filters coated with extracellular matrix (ECMatrix gel) on the upper surface were obtained from BD Biosciences.7
The experiments were performed according to the manufacturer’s protocol. Cells (1.84 x 105) were added to the upper chamber in serum-free medium containing 0.1% BSA, and the total invasive cells in the lower chamber were counted after 48 h of incubation at 37°C with 5% CO2.
Confocal Microscopy.
The pools of cells stably expressing EGFP-PRLs were seeded onto glass coverslips and grew for 24 h. Cells were washed twice with PBSCM and then fixed in 3% paraformaldehyde for 20 min at room temperature. After three more washes with PBSCM, the cells were permeabilized for 15 min with 0.1% saponin in the same buffer. Cells were washed three times with PBSCM and incubated with TRITC-conjugated Phalloidin (Molecular Probes) for 1 h. The cells were washed four times with PBSCM and mounted onto a glass slide with one drop of antifade reagent in PBS glycerol (Biomedia Corp., Foster City, CA), and kept at 4°C in the dark until analysis. Confocal imaging was performed using a laser scanning head (MRC 1024; Bio-Rad Laboratories, Hertfordshire, United Kingdom).
Live Cell Imaging.
Cells (5 x 105) were seeded onto each 35-mm glass bottom dish (MatTek Co., Ashland, MA) and cultured at 37°C with 5% CO2 for 24 h. The confluent monolayer of cells was wounded as described in the legend to Fig. 2
, and the culture medium was then replaced with HEPES-buffered serum-free medium. Cell movement was monitored with a Nikon inverted microscope using a x40 oil lens. The microscope was equipped with a homemade temperature control chamber set at 37°C. Time-lapse series of images were captured using a Bio-Rad Radiance 2000 confocal system and analyzed using LaserPix software (Bio-Rad).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. Heterologous protein expression was achieved by transfection of the cells with the tetracycline-responsive pStar vector containing the appropriate cDNA (3
, 7)
. Tetracycline-enhanced overexpression of Myc-PRL-1 or -3 was toxic to the cells, but a significant level of Myc-PRL-1 or -3 was constitutively expressed in these stable cell lines without tetracycline induction (Fig. 1C)
. Thus, we focused on determining the effect of the constitutive levels of Myc-PRL-1 and -3 expression on cell migration and invasion. When cell motility was examined using the standard Transwell assay (8)
, 
5-fold more Myc-PRL-1- and -3-expressing cells migrated to the bottom chamber than did the control ß-gal-expressing cells (Fig. 2A)
. The invasive capacities of the cells were assessed using Transwells with filters coated with extracellular matrix gel (8
, 9)
, and were found to be enhanced 8-fold by Myc-PRL-1 or -3 expression compared with control ß-gal-expression (Fig. 2B)
. To confirm these observations, cell motility was independently assessed by wound-healing assays (10)
. As shown in Fig. 3A
, Myc-PRL-1- and -3-expressing cells migrated much faster than ß-gal-expressing cells. The Myc-PRL-expressing cells migrated a 5-cell distance, whereas the ß-gal control cells migrated only 1-cell distance during a 5-h incubation after wounding. Thus, Myc-PRL-3 and -1 cells have greatly enhanced motility and invasive ability as compared with control cells. To more exactly measure the velocity of cell motility for these cell lines, live cell time-lapse imaging analysis was performed on Myc-PRL-3 cells (Supplementary Data, video 1) and control ß-gal cells (Supplementary Data, video 2) for 400 min. Images obtained at the start and end of this time period are shown in Fig. 3B
. The front line of the Myc-PRL-3 cell sheet at the wound edge moved much faster than did that of control ß-gal cells. The movement of individual cells at the leading edge was tracked manually using LaserPix software (Bio-Rad). The velocities of Myc-PRL-3-expressing cells and control ß-gal-expressing cells were calculated, respectively, as 14.70 ± 4.41 µm/h and 5.04 ± 2.08 µm/h (P < 0.00001, by Student’s t test; Fig. 3C
).
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. These structures have been demonstrated to play a role in cell movement (11)
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(fluorescence) and B (phase contrast). Examination of EGFP-PRL-3 localization showed that it was concentrated at membrane structures (ruffles and protrusions; Fig. 5A
) that were dynamic during cell movement (Supplementary Data, video 3). The EGFP-PRL-3 (C104S) was similarly associated with membrane structures (Fig. 5A
; Supplementary Data, video 4); however, reduced motility was noted in EGFP-PRL3 (C104S) -expressing cells as compared with EGFP-PRL-3-expressing cells. By tracking individual cells, the average calculated velocities for EGFP-PRL-3 and EGFP-PRL-3 (C104S) cells were 24.01 ± 3.55 µm/h and 12.86 ± 4.99 µm/h, respectively (P < 0.0005, Student’s t test; Fig. 5C
).
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. Ten of 10 mice carrying PRL-3-expressing cells had more extensive lung tumors; in addition, 2 of them had liver metastasis tumors (Fig. 6)
. In contrast, no tumors were found in 10 mice injected with ß-gal-expressing cells (Fig. 6)
. Human colon cancer cells are taken by the hepatic-portal circulatory system first to the liver, the primary site of metastasis. In our experimental metastasis assay, cells injected into the tail vein initially arrive in the lung.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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5-fold. Secondly, qualitative wound-healing assays and live-cell imaging studies supported this conclusion. Furthermore, the velocity of migration of Myc-PRL-3 expressing cells was 3-fold higher than the ß-gal-expressing control cells. In addition to increased motility, the Myc-PRL-3- and Myc-PRL-1-expressing cells exhibited an 8-fold increase in invasive abilities over the control ß-gal-expressing CHO cells as assessed by an ECMatrix gel-membrane coated Transwell assay. As CHO cells have no detectable endogenous PRL expression (Fig. 1)
, the crucial event that induced the gain of motile and invasive properties by the CHO cells was the expression of PRL-1 or -3. This conclusion was additionally strengthened and extended by our studies of independently and differently generated CHO cells stably expressing wild-type active PRL-3 or a catalytically inactive PRL-3 (C104S) mutant. In this system, PRL-3 was tagged with EGFP instead of Myc and expressed using the pEGFP-C1 instead of the pSTAR plasmid vector. Also, pools of these stably transfected cells were used for analysis to avoid clonal variations. Notably, EGFP-PRL-3 expression dramatically enhanced cell migration, whereas mutant EGFP-PRL-3 (C104S) expression had a greatly reduced effect on promoting cell migration, suggesting that the phosphatase activity of PRL-3 is required for optimal PRL-3-dependent migration. The CHO-EGFP-PRL-3 cell pool exhibited a higher velocity of migration than the CHO-Myc-PRL-3 cell line (24.01 ± 3.55 versus 14.70 ± 4.41 µm/h, respectively). This could be because of an inherent effect of EGFP on the cells. Alternatively, it may be because of different PRL-3 expression levels driven by different promoters (cytomegalovirus promoter of pEGFP-C1 versus the uninduced tetracycline-inducible operator mini promoter of pSTAR) or gene copy numbers. In support of this, we observed that cells with different EGFP-PRL-3 expression levels showed different morphology and motility: the higher the expression levels, the faster the cells moved. Also, the PRL-3 gene was found in multiple copies within a small amplicon in 25% of actual colorectal cancer liver metastases (6) , indicating that gene amplification is an important mechanism to effect elevated PRL-3 expression in metastases. Interestingly, our independent experiments revealed a difference in migration velocity between the CHO-EGFP-PRL-3 (C104S) cell pool and the control CHO-ß-gal cell line (12.86 ± 4.99 versus 5.04 ± 2.08 µm/h, respectively), either because of an inherent EGFP effect or raising the possibility that high levels of EGFP-PRL-3 (C104S) expression could enhance cell motility in a phosphatase-independent manner. Nevertheless, both Myc-PRL-3- and EGFP-PRL-3-expressing cells demonstrated enhanced cell motility compared with their respective ß-gal- or EGFP-PRL-3- (C104S) expressing control cells by 3-fold and 2-fold.
The rapid metastasis in our animal study suggests that PRL-3 and -1 can act as key players to initiate and maintain tumor cell growth in a "foreign territory." Examination of the expression levels of PRL-1, -2, and -3 in other metastatic tumors will provide insight regarding the possibility that these PRL-PTPs, and perhaps PRL-2, could be associated in general with metastatic events. The discovery that PRL-3 is overexpressed in all of the examined metastatic colorectal cancers (6) indicates that PRL-3 is a potential molecular marker for clinical estimation of tumor aggressiveness. This, together with our present study demonstrating that PRL-3 overexpression promotes cellular properties associated with metastasis as well as the end point formation of macroscopic tumors in an in vivo metastasis assay, suggest that PRL-3 may additionally present an excellent target for intervention with colorectal tumor metastasis. This could be an important new therapeutic opportunity, because most of the described genetic alterations in colorectal cancers involve the inactivation of tumor suppressor genes, which are difficult to target with drugs (18 , 19) . Because optimal PRL-3-enhanced cell migration is dependent on preservation of its catalytic function, the consensus phosphatase motif will potentially be a therapeutic target. Also, the prenylation-dependent association of the PRL-PTPs with cell membranes (3) , coupled with the present description of the association of PRL-3 with membrane structures including ruffles, protrusions, and some vacuolar-like membrane extensions could represent another opportunity for intervention. These membrane structures have been demonstrated to play a role in cell movement and invasion (10 , 11) . The expression of membrane-associated PRL-3 may induce dephosphorylation of target substrates at the cell membrane to modulate the organization of the plasma membrane in such a way to promote cell motility and invasion. No protein substrate has yet been identified for PRL-3, and classic in vitro phosphatase substrates are poorly dephosphorylated by recombinant PRL-3.8 This latter property is similar to PTEN, a 3'-lipid phosphatase of phosphoinositides (20) . Because PRL-1, -2, and -3 share some homology with PTEN in the phosphatase active site "signature motif" and flanking regions (1) , one might speculate that PRL-3, like PTEN, acts as a lipid phosphatase at the cytoplasmic face of the plasma membrane. Our data raise the possibility that disruption of this prenylation-dependent association could effectively block the function(s) of PRL-3 in cell migration and invasion. In this regard, we have shown previously that treatment of cells with the prenyltransferase inhibitor FTI-277 (which specifically inhibits protein farnesylation; Ref. 21 ) induces the subcellular redistribution of PRLs from plasma membrane to the nucleus (3) . Notably, some reports support the potential use of farnesyltransferase inhibitors as antimetastatic agents in cancer therapy (22 , 23) . It will be of considerable interest to determine whether such inhibitors of prenylation affect PRL-3- or PRL-1-dependent cell migration, invasiveness, and metastasis in our cell model system. In conclusion, the viability of PRL-3 as an antimetastatic target warrants assessment.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by research grants from The Agency of Science, Technology and Research (A* STAR), Singapore. 
2 Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org).
3 To whom requests for reprints should be addressed, at Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore. Phone: 65-6874-3752; Fax: 65-6779-1117; E-mail: mcbzengq{at}imcb.nus.edu.sg
4 The abbreviations used are: PRL, phosphatase of regenerating liver; CHO, Chinese hamster ovary; PTP, protein-tyrosine phosphatase; ß-gal, ß-galactosidase; FBS, fetal bovine serum; EGFP, enhanced green fluorescent protein; PBSCM, PBS with CaCl2 and MgCl2; TRITC, tetramethylrhodamine isothiocyanate; PTEN, phosphatase and tensin homolog deleted in chromosome 10.
5 Internet address: http://www.clontech.com/index.shtml.
6 Internet address: http://www.corning.com.
7 Internet address: http://www.bdbiosciences.com/index.shtml.
Received 1/ 6/03. Accepted 3/20/03.
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