scholarly journals The Expression of PRL-3 Correlates With Chromosomal Instability in Colon Cancer and Thyroid Cancer

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 208s-208s
Author(s):  
S. Lian ◽  
L. Meng ◽  
Y. Yang ◽  
L. Qu ◽  
C. Shou

Background: Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We have reported that PRL-3 recruits to telomeric DNA by RAP1/TRF2 protein. Overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomere, telomere deprotection, DNA damage response, chromosomal instability. Aim: To substantiate the previous results and further assess the physiologic relevance of PRL-3 in tumorigenesis, also to explore the prediction role PRL-3 in clinical patients. We detected the expression of PRL-3, telomere length, H3K9me and p-H2AX in the colon cancer and thyroid cancer samples. Methods: We collected 273 colorectal cancer patients and stained with PRL-3 antibody and counterstained with HE. Semiquantitative scoring was performed. Microscopic analysis was done by 2 of the authors. Tissues-chips were obtained from Alenabio (Th802a, thyroid). Results: We retrospectively analyzed a cohort of colorectal cancer tissues (n = 269) stained with anti-PRL-3 (clone 3B6). Although the majority of mitotic cells were bipolar, more multipolar mitoses, an indicator of chromosomal missegregation and chromosomal instability, was observed in PRL-3 positive tissues than in negative tissues (Fig 1A). Also in the PRL-3 positive tissues, more anaphase bridges were detected ( Fig 1A ). These results suggest that PRL-3 levels positively correlate with chromosomal instability in colon cancer tissues. Next, we analyzed 12 freshly dissected colon cancer tissues, with WI38 control and PRL-3-overexpressing cells as reference samples. We detected varying levels of PRL-3 proteins in these tissues, and the level of stably overexpressed PRL-3 in WI38 cells was comparable to some of these tissues. An inverse correlation between PRL-3 and telomere length was revealed, while PRL-3 showed positive correlations with gamma-H2AX and H3K9me3 ( Fig 1B ). We also performed quantitative FISH (qFISH) analysis of telomere length and immunohistochemical staining of PRL-3 with thyroid tissue chips containing 80 samples. We found decreased telomere staining in adenocarcinoma tissues (n = 40) with positive PRL-3 expression, particularly in those of stage I (n = 23) ( Fig 1C ). No correlation was observed in thyroid adenoma (n = 40) or stage II/III/IV adenocarcinoma (n = 17) ( Fig 1C ). With the same thyroid tissue-chip, we evaluated association between PRL-3 and senescence. In stage I thyroid adenocarcinoma tissues, positive staining of PRL-3 correlated with positive H3K9me3 staining, but such correlation was not observed in thyroid adenoma or Stage II/III/IV adenocarcinoma ( Fig 1D ). Conclusion: These results raise the possibility that PRL-3-promoted telomere deprotection and senescence are early events during the development and progression of cancer. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.[Figure: see text]

Swiss Surgery ◽  
2003 ◽  
Vol 9 (1) ◽  
pp. 3-7 ◽  
Author(s):  
Gervaz ◽  
Bühler ◽  
Scheiwiller ◽  
Morel

The central hypothesis explored in this paper is that colorectal cancer (CRC) is a heterogeneous disease. The initial clue to this heterogeneity was provided by genetic findings; however, embryological and physiological data had previously been gathered, showing that proximal (in relation to the splenic flexure) and distal parts of the colon represent distinct entities. Molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in CRC progression. In summary, there may be not one, but two colons and two types of colorectal carcinogenesis, with distinct clinical outcome. The implications for the clinicians are two-folds; 1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI-positive lesions; and 2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in future trials of adjuvant chemotherapy in patients with stage II and III colon cancer.


2018 ◽  
Vol 84 (4) ◽  
pp. 565-569 ◽  
Author(s):  
Yasumitsu Hirano ◽  
Masakazu Hattori ◽  
Kenji Douden ◽  
Chikashi Hiranuma ◽  
Yasuo Hashizume ◽  
...  

Single-incision laparoscopic surgery (SILS) has been developed with the aim to further reduce the invasiveness of conventional laparoscopy. Our experiences with more than 300 consecutive patients with SILS for colon cancer are reviewed, and its outcomes are evaluated to determine the midterm clinical and oncologic safety of SILS for colon cancer in a community hospital. A single surgeon's consecutive experience of SILS for colon cancer is presented. Three hundred and eight patients were treated with the SILS procedure for colon cancer between December 2010 and March 2015. Data were analyzed according to intention to treat. Of these 308 patients, 19 (6.2%) were converted to laparotomy. Intraoperative injury occurred in five patients. Postoperative complications occurred in 19 patients (6.2%). The 2-year relapse-free survival rates of patients with Stage I, Stage II, and Stage III were 97.8, 92.2, and 80.4 per cent, respectively, and the 2-year overall survival rates of patients with Stage I, Stage II, Stage III, and Stage IV were 100, 95.7, 93.0, and 74.4 per cent, respectively. Our initial experiences showed that SILS colectomy for cancer can be performed safely and with good short-term oncologic outcomes by a skilled surgeon.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4036-4036
Author(s):  
A. M. Glas ◽  
P. Roepman ◽  
R. Salazar ◽  
G. Capella ◽  
V. Moreno ◽  
...  

4036 Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy. [Table: see text]


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2599-2599
Author(s):  
Susan Spillane ◽  
Kathleen Bennett ◽  
Linda Sharp ◽  
Thomas Ian Barron

2599 Background: Preclinical studies have suggested a role for metformin in the treatment of colorectal cancer (CRC). Associations between metformin versus sulfonylurea exposure and mortality (all-cause and colorectal cancer specific) are assessed in this population-based study of patients with a diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland records were linked to prescription claims data and used to identify a cohort of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From this cohort, 2 patient groups were identified and compared for outcomes - those who received a prescription for metformin +/- a sulfonylurea (MET) or a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models adjusted for age, sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin or statin exposure. Analyses were repeated stratifying by stage and site. Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 received a prescription for metformin or a sulfonylurea in the 90 days pre diagnosis (median follow-up 1.6 years; MET: n=257; SUL: n=112). In adjusted analyses metformin exposure was associated with a 28% lower risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in colon cancer, metformin exposure was associated with a significant one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 0.40-1.02). No mortality benefit was observed for rectal cancer. The association between metformin exposure and reduced mortality was strongest for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: Pre-diagnosis metformin exposure in CRC patients was associated with a significant reduction in mortality relative to sulfonylurea exposure. This benefit was greatest in patients with colon cancer and early stage disease.


2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 429-429
Author(s):  
Riccardo Giampieri ◽  
Mario Scartozzi ◽  
Cristian Loretelli ◽  
Alessandra Mandolesi ◽  
Alessandro Bittoni ◽  
...  

429 Background: Although disease stage is the most relevant factor influencing treatment choice in locally advanced radically resected colon cancer, it is not uncommon to observe disease relapse in patients with apparent low risk stage that are usually excluded from an adjuvant therapy. On the contrary we also know that some patients with high risk stage are not likely to relapse, independently from medical treatment received. Preclinical data suggested that cancer stem cells may influence the biological behaviour of many solid tumours including colorectal cancer, we then tested a panel of genetic markers of stemness in resected Dukes stage B and C colorectal cancer patients in order to define a prognostic profile. Methods: We performed k-means unsupervised clustering (K=2) using the mRNA expression data of 66 genes. The algorithm divided the patients into two groups (A and B). Most patients clustered in a manner consistent with relapse free survival, defined as the time between primary surgery and first radiological sign of metastatic involvement or patients death, whichever came first. Results: A total of 62 patients were analysed (36, 58% stage II and 26, 41% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and B. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Interestingly, even if group A had a worse outcome in terms of risk of relapse, an higher proportion of stage II patients could be found in this group (83%) when compared with the group B (52%). Among tested genes, those with the highest capability in determining allocation into one of the two groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. Conclusions: This analysis supports the idea that, other than (or maybe more than) stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients. Our findings may also be relevant for new treatment strategies targeting tumour stem cells genetic profile.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 867-867
Author(s):  
Shusuke Yagi ◽  
Eiji Shinozaki ◽  
Keisho Chin ◽  
Mitsukuni Suenaga ◽  
Daisuke Takahari ◽  
...  

867 Background: CAPOX as adjuvant chemotherapy is a standard care option for stage III and high risk stage II colorectal cancer(CRC). And then chemotherapy induced diarrhea (CID) is known as one of the dose-limiting toxicities for CAPOX. Although diverting ileostomy is useful for preventing serious complications of high risk anastomosis, it is well recognized that high ileostomy output is hard to manage. Furthermore, the effect of diverting ileostomy on CID of adjuvant chemotherapy is unclear. In this study, we addressed the clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for CRC. Methods: Patients who diagnosed with stage III colon cancer and stage II or III rectal cancer after curative surgery and received CAPOX as adjuvant chemotherapy during 2011- 2014 were reviewed retrospectively. We investigated the relationship between diverting ileostomy and dose intensity, toxicities and disease-free survival (DFS). Results: 112 patients (median age 60 years, 52% male, 69% colon cancer, 63% stage III, median follow-up 47 months) were enrolled in this study. Of 112 patients, 100 patients were received chemotherapy without ileostomy (non-ileostomy group: NIG) and 12 patients were received chemotherapy with ileostomy (ileostomy group: IG). 112 Patients received 870 chemotherapy cycles. All treatment related grade 3/4 adverse events were documented in 39% of patients in NIG and 33% of patients in IG (P = 0.77). Grade 3/4 of CID occurred in 8% of patients in NIG and 8% of patients in IG (P = 1). Grade 3/4 of neutropenia were recognized in 21% of patients in NIG and 17% of patients in IG (P = 1). Average relative dose intensity (RDI) in NIG were 75.7% and 85.8% for capecitabine and oxaliplatin, respectively. Average RDI of capecitabine and oxaliplatin in IG were 76.1% and 82.7%, respectively. Significant difference of RDI of capecitabine and oxaliplatin were not shown in comparison between NIG and IG (P = 0.93, P = 0.63). The 3-year DFS rate was 85.0% in NIG and 75.0% in IG. The HR for DFS for NIG compared to IG was 1.709 (95% CI, 0.49 to 5.95; P = 0.40). Conclusions: The presence of diverting ileostomy does not affect RDI of CAPOX as adjuvant chemotherapy.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3609-3609
Author(s):  
Lucy Gately ◽  
Christine Semira ◽  
Azim Jalali ◽  
Ian Faragher ◽  
Sumitra Ananda ◽  
...  

3609 Background: Multiple meta-analyses have demonstrated that routine surveillance following curative intent colorectal cancer surgery improves overall survival. This benefit is largely driven by early detection and curative intent resection of oligometastatic disease. Intuitively, any surveillance benefit should be proportional to recurrence risk, leading some to question the value of surveillance for stage I patients where recurrence rates are low. However, the survival benefit of surveillance has not previously been reported by stage. Methods: We explored data from a multi-site cohort of colorectal cancer patients (pts) diagnosed from 1 January 2001 to 31 December 2016. Pts were followed according to standard protocols with a standardized comprehensive outcome data captured prospectively. Pts with a rectal primary or metastatic disease at presentation were excluded from the analysis. We examined the correlation of stage at diagnosis with tumor recurrence and subsequent outcomes. Results: Of 3608 colon cancer pts, 690 (19%) had stage 1, 1580 (44%) had stage 2, and 1338 (37%) had stage 3 disease. Median follow-up was 7.8 years. Stage at diagnosis impacted recurrence rate (4% stage I vs 12% stage II vs 28% stage III, p < .0001) but not median time to recurrence. Recurrence patterns varied with stage (e.g. distant nodal disease 5% vs 7% vs 16%, p = .003; liver metastases 90% vs 53% vs 42%, p = 0.001). In pts with recurrence, resection of oligometastatic disease varied significantly by stage (58% vs 42% vs 30%, p < .0001) as did post-resection 5 year survival (91% vs 66% vs 43%, p < 0.001). In pts with recurrence treated with palliative intent, stage at diagnosis also impacted post-recurrence 5 year survival (11% vs 7% vs 5%, p < 0.03). Conclusions: Colon cancer stage at diagnosis substantially impacts the proportion of pts able to undergo curative intent surgery for surveillance detected recurrent disease, potentially driven by stage specific metastatic patterns. Stage at diagnosis also has a significant impact on post-resection survival outcomes potentially driven by stage specific biology. Our data indicate a far greater survival impact of surveillance for stage I colon cancer than would be anticipated based on recurrence rate alone.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16145-e16145
Author(s):  
Herbert A. Fritsche ◽  
Jason Lee Liggett ◽  
Hong Zhang ◽  
Linnea Ferm ◽  
Ib Jarle Christensen ◽  
...  

e16145 Background: Colorectal cancer (CRC) is the second leading cancer worldwide in terms of incidence, 5-year prevalence and mortality for both women and men ages 45 years old and up. The current screening method for many countries with organized screening programs is the FIT test for fecal occult blood; however, this test can result in false positive rates as high as 65%. A FIT reflex test could reduce unnecessary colonoscopies while reducing wait times for those patients that need confirmatory colonoscopies the most. Methods: Danish FIT positive colonoscopy confirmed serum samples (n = 1,499) were divided into training and validation sets maintaining approximately equivalent percentages of clean colonoscopy (40%), low risk adenomas (16%), medium risk adenomas (19%), high risk adenomas (13%), stage I CRC (5%), stage II CRC (2%), stage III CRC (4%), and stage IV CRC (0.5%). Proteins were quantified by custom 16-plex immunoassays utilizing the Luminex xMAP platform. A support vector machine supervised machine learning algorithm was trained with the 16 biomarkers plus age and FIT concentration using 1,291 samples for the outcome medium risk adenoma, high risk adenoma, and CRC. Then this algorithm was tested on a blind 208 sample validation set. Results: The training set was 90% sensitive and 27% specific (AUC = 0.68) and the validation set was 93% sensitive and 21% specific (AUC = 0.63). The sensitivities of the validation by risk/stage was as follows: medium risk adenoma 91%, high risk adenomas 92%, stage I CRC 100%, stage II CRC 100%, stage III CRC 100%, stage IV CRC 93%. Conclusions: This study demonstrates feasibility of a novel blood-based multiplex protein immunoassay for use as a reflex to FIT positive results in population wide screening. It detected nearly all adenomas and carcinomas while reducing FIT false positives and thus unnecessary colonoscopies by more than 20%. A FIT reflex test could alleviate endoscopy burden experienced in countries with organized cancer screening programs, while providing better patient outcomes by detecting polyps and early-stage CRC with high sensitivity.


2020 ◽  
Author(s):  
Fuda Huang ◽  
Mingwei Wei ◽  
Anmin Wang ◽  
Ya Zhang ◽  
Zebang Qin ◽  
...  

Abstract BackgroundCalponin was first defined as a striated muscle troponin T-like protein that binds actin thin filaments to regulate smooth muscle contraction. There are few studies of CNN1 and CNN2 in colorectal cancer, and the roles these two genes play in colorectal cancer cell lines and the mechanisms by which they act are unknown.MethodsWe used immunohistochemistry to identify expression of the two genes in the cancer tissues. RT-PCR was used to measure expression levels of microRNA. W performed western blots to measure changes in signaling pathways in the context of expression interference.Meanwhile, the same method was used to measure binding relationship between the two genes and key pathway proteins. To determine the relationship between microRNA and gene mRNA, we used the reporter gene method. We used the chi-square and t-test methods to analyze the significance and correlations of the data.Results and conclusionsExpression levels of CNN1 were lower in colon cancer tissues than in normal mucosal tissues. After downregulating CNN1, the cell cycle in colon cancer cell lines progressed quickly, and the expression of related pathway proteins also increased. Expression levels of CNN2 were higher in colon cancer tissues, and its downregulation significantly inhibited cell cycle progression in colon cancer cell lines. We confirmed correlations between the expression of microRNA and CNN2 using data analysis.Bars indicate ± standard errors.*p < 0.05; **p < 0.01 compared with the control. The inhibition of the expression of CNN2 mRNA using microRNA was confirmed using western blot. The combination of the two at the mechanism level was also demonstrated using the reporter gene method.


Author(s):  
Yang zhi Jiang ◽  
Qing Guo Tao ◽  
fei yan Zhu

BACKGROUND AIM To explore the correlation between the expression of miRNA-135a and Bach1 in colorectal cancer tissue and the patient's clinical information.  Methods   60 patients with colorectal carcinoma were treated as a control group. Real-time quantitative PCR assays and immunohistochemistry method were performed to detect the expression of miRNA-135a and Bach1 in 60 colorectal carcinomas and adjacent normal tissues, and the clinical and pathological classifications had also been investigated. The SPSS 19.00 software was used. All data represented mean±SD of three independent experiments. P&lt;0.05 was considered statistically significant. Results  miRNA-135a expression levels increased significantly in the colon cancer tissues compared with the non-tumor control tissues(P&lt;0.01). miRNA-135a expression levels were higher in stage III/IV than in stage I/II colon cancer patients. The expression level of Bach1 in colorectal cancer was significantly lower(P&lt;0.01). Bach1 and miRNA-135a were negatively correlated.  Conclusions:  The levels of miRNA-135a and Bach1 were opposite, the over-expression of miRNA-135a might downregulated the expression of Bach1, which might be involved in the pathogenesis of colorectal cancer.


Sign in / Sign up

Export Citation Format

Share Document