| 31. |
- Kopsida, Maria, et al.
(author)
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RhoB expression associated with chemotherapy response and prognosis in colorectal cancer
- 2024
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In: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 24:1
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Journal article (peer-reviewed)abstract
- Purpose: To examine the role of RhoB expression in relation to chemotherapy response, clinical outcomes and associated signaling pathways in colorectal cancer patients.Materials and methods: The study included 5 colon cancer cell lines, zebrafish embryos and 260 colorectal cancer patients treated with 5-fluorouracil (5-FU) and oxaliplatin (OXL). The methods consisted of CRISPR/Cas9, reactive oxygen species (ROS), caspase-3 activity, autophagy flux, in-silico RNA sequencing and immunohistochemistry. Gene expression analysis and pathway analysis were conducted using RNA-seq data.Results: All cancer lines tested, including SW480, SW480-KO13 (RhoB knockout), SW480-KO55 (RhoB knockout), HCT116 and HCT116-OE (RhoB overexpressed), exhibited cytotoxicity to 5-FU and OXL. RhoB knockout cell lines demonstrated significantly reduced migration compared to the control cell lines. Furthermore, RhoB played a role in caspase-3-dependent apoptosis, regulation of ROS production and autophagic flux. The mRNA sequencing data indicated lower expression levels of oncogenes in RhoB knockout cell lines. The zebrafish model bearing SW480-KO showed a light trend toward tumor regression. RhoB expression by immunohistochemistry in patients was increased from normal mucosa to tumor samples. In patients who received chemotherapy, high RhoB expression was related to worse survival compared to low RhoB expression. Furthermore, the molecular docking analysis revealed that OXL had a higher binding affinity for RhoB than 5-FU, with a binding affinity of -7.8 kcal/mol and HADDOCK predicted molecular interactions between RhoB and caspase 3 protein. Gene-set enrichment analysis supported these findings, showing that enrichment of DNA damage response pathway and p53 signaling in RhoB overexpression treatment group, while the RhoB knockout treatment group exhibited enrichment in the negative regulation pathway of cell migration.Conclusion: RhoB was negatively associated with chemotherapy response and survival in colorectal cancers. Therefore, RhoB inhibition may enhance chemotherapeutic responses and patient survival.
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| 32. |
- Kotti, Angeliki
(author)
-
Clinical and Biological Factors Related to Survival in Patients with Rectal Cancer
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Rectal cancer is a common malignancy within the gastrointestinal tract. Despite the advances in diagnosis and treatment of rectal cancer patients during the last decades, there are still many patients who die from their disease. In order to personalise the therapy and optimise the clinical outcomes, it is important to identify factors that have an impact on survival of rectal cancer patients. Therefore, the overall aim of this thesis was to identify clinical and biological factors that were related to survival in patients with rectal cancer. Paper I aimed to evaluate the impact of statins on survival in older and younger patients with rectal cancer. The study included 238 older patients (≥70 years) and 227 younger patients (<70 years) from the southeast healthcare region of Sweden. The patients were classified as statin users if they used any type of statins at the time of the cancer diagnosis. In the older group, statin users had better cancer-specific survival, disease-free survival, and overall survival compared with non-users. No such association was present in the younger group. Paper II aimed to evaluate the impact of computed tomography (CT)-measured body composition on survival in rectal cancer patients. The study included 173 patients from the region Ostergotland of Sweden who underwent a CT colonography at the time of diagnosis. Skeletal muscle index (SMI) and visceral adipose tissue area (VAT) were quantified at the level of the third lumbar vertebral body, using the CT colonography acquired at the time of diagnosis. The patients were divided into a low or high SMI group, and a low or high VAT group. Low SMI was related to worse survival compared to high SMI in all the patients. High VAT was related to better survival in men with low or middle rectal cancer, while high VAT was related to worse survival in women with low or middle rectal cancer. Paper III aimed to evaluate the prognostic value of SPARCL1 expression in patients with rectal cancer with a focus on radiotherapy (RT). The study included 138 patients with rectal cancer who participated in the Swedish Rectal Cancer Trial. Of those, 63 patients underwent both preoperative RT and surgery, while 75 patients had surgery alone. SPARCL1 expression was determined by immunohistochemistry. Strong SPARCL1 expression was related to better overall survival compared to weak SPARCL1 expression in patients with stage III disease who received RT, but not in patients with stage III disease who did not receive RT. Moreover, SPARCL1 expression was increased in primary tumours with RT compared to tumours without RT. In summary, statin use was related to improved survival in older patients with rectal cancer. CT-measured body composition parameters provided useful information for determining the prognosis of rectal cancer patients. SPARCL1 was identified as a potential prognostic biomarker in rectal cancer patients who received preoperative RT. Conclusively, the results of this thesis indicate that statin drugs, CT-measured body composition and SPARCL1 are factors related to survival in patients with rectal cancer. The evidence may benefit patients by more accurate estimating of their prognosis, personalised treatment and improved clinical outcomes.
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| 33. |
- Lewander, Andreas, 1973-, et al.
(author)
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Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations
- 2007
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 42:11, s. 1332-1338
-
Journal article (peer-reviewed)abstract
- Objective. An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. Material and methods. Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with ≥3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Results. The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR=3.81, 95% CI: 2.17-6.69, p<0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p<0.0001 for homozygote deletion) and sporadic cancer patients (OR=7.73, 95% CI: 3.06-19.57, p<0.0001 for heterozygote deletion, and OR=6.58, 95% CI: 2.35-18.43, p<0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p>0.05). Similar evidence was seen in age-adjusted analyses (p<0.0001). The polymorphism did not correlate to clinicopathological variables (p>0.05). Conclusions. Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients. © 2007 Taylor & Francis.
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| 34. |
- Liu, Na, et al.
(author)
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Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.
- 2017
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In: Oncotarget. - : Impact journals. - 1949-2553. ; 8:36, s. 60015-60024
-
Journal article (peer-reviewed)abstract
- Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.
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| 35. |
- Meng, N, et al.
(author)
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RECK, a novel matrix metalloproteinase regulator
- 2008
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In: Histology and Histopathology. - : Hernandéz. - 0213-3911 .- 1699-5848. ; 23:8, s. 1003-1010
-
Research review (peer-reviewed)abstract
- Extracellular matrix (ECM) macromolecules are important for creating the cellular environments required during development and morphogenesis of tissues. Matrix metalloproteinases (MMPs) are a family of Zn-dependent endopeptidases that collectively are capable of cleaving virtually all ECM substrates, and play an important role in some physiological and pathological processes. MMP activity can be inhibited by some natural and artificial inhibitors. A newly found membrane-anchored regulator of MMPs, the reversion-inducing-cysteine-rich protein with kazal motifs (RECK), is downregulated when the cells undergo a process of malignant transformation, and is currently the subject of considerable research activity because of its specific structure and function. In this review, we have chosen to concentrate our efforts on the structure, function, regulation, and future prospect of RECK in order to provide a new target for prevention and treatment of tumours
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| 36. |
- Meng, Wen-Jian, et al.
(author)
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Microsatellite instability did not predict individual survival in sporadic stage II and III rectal cancer patients
- 2007
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In: Oncology. - : S. Karger AG. - 0890-9091 .- 0030-2414 .- 1423-0232. ; 72:1-2, s. 82-88
-
Journal article (peer-reviewed)abstract
- Objectives: Tumors with high-frequency microsatellite instability (MSI-H) have unique biological behavior and the predictive role of microsatellite instability (MSI) status on survival of colorectal cancer is still debated. The prognostic significance of MSI status in sporadic stage II and III rectal cancer patients needs to be more precisely defined. So we investigated the relationship between MSI status and clinicopathological features and prognosis in these patients. Methods: DNAs from fresh-frozen paired samples of tumors and corresponding normal tissue from 128 stage II and III rectal cancer patients were analyzed for MSI by PCR amplification using markers recommended by a National Cancer Institute workshop on MSI. To assess prognostic significance, Cox proportional hazards modeling was used. Results: Twelve (9.3%) tumors in our study were MSI-H, 28 (21.9%) were low-frequency MSI (MSI-L) and 88 (68.8%) were microsatellite stable (MSS). Most of the MSI-H tumors compared with MSI-L and MSS tumors were found in female patients (p = 0.031), had mucinous histology (p = 0.023), high grade of differentiation (p = 0.002) and high level of preoperative serum carcinoembryonic antigen (p = 0.005). Rectal cancer patients with MSI-H did not show a better clinical outcome than those with MSI-L/MSS, neither in all cases (p = 0.986) nor in stage II and stage III disease analyzed separately (p = 0.705 and p = 0.664, respectively). Conclusions: Data provided here demonstrated there was high incidence of MSI-H and MSI was not a prognostic factor in sporadic stage II and III rectal cancers from the Chinese Han population included in this study. Tumor stage is more suitable than MSI status for prediction of individual survival in sporadic stage II and III rectal cancer patients. Copyright © 2007 S. Karger AG.
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| 37. |
- Meng, Wen-Jian, et al.
(author)
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Novel mutations and sequence variants in exons 3-9 of human T Cell Factor-4 gene in sporadic rectal cancer patients stratified by microsatellite instability
- 2007
-
In: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 13:27, s. 3747-3751
-
Journal article (peer-reviewed)abstract
- Aim: To establish the role of human T Cell Factor-4 (hTCF-4) gene exons 3-9 mutation status in association with sporadic rectal cancer with microsatellite instability (MSI). Methods: Microsatellite markers were genotyped in 93 sporadic rectal cancer patients. Eleven cases were found to be high-frequency MSI (MSI-H). Sequence analysis of the coding region of the exons 3-9 of hTCF-4 gene was carried out for the 11 MSI-H cases and 10 controls (5 microsatellite stability (MSS) cases and 5 cases with normal mucosa). The sequencing and MSI identification were used. Results: Several novel mutations and variants were revealed. In exon 4, one is a 4-position continuous alteration which caused amino acid change from Q131T and S132I (391insA, 392 G > A, 393 A > G and 395delC) and another nucleotide deletion (395delC) is present in MSI-H cases (5/10 and 4/10, respectively) but completely absent in the controls. Conclusion: Novel mutations in exon 4 of hTCF-4 gene were revealed in this study, which might be of importance in the pathogenesis of sporadic rectal cancer patients with MSI-H. © 2007 WJG. All rights reserved.
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| 38. |
- Moparhti, Satish Babu, et al.
(author)
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Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers
- 2007
-
In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 30:1, s. 91-95
-
Journal article (peer-reviewed)abstract
- MAC30 is highly expressed in several types of tumors including colorectal cancers, however, its clinicopathological and biological significance in colorectal cancers is currently not known. The aim of our study was to investigate MAC30 expression in distant normal mucosa, adjacent normal mucosa, primary tumors and metastases of colorectal cancer, and to determine the relationship between MAC30 expression and clinicopathological and biological variables. MAC30 expression was immunohistochemically examined in distant normal mucosa (n = 54), adjacent normal mucosa (n = 123), primary tumors (n = 217) and lymph node metastases (n = 56) from colorectal cancer patients. MAC30 cytoplasmic expression was increased from distant normal mucosa to primary tumor and to metastasis (p < 0.0001-0.04). Furthermore, 40% primary and 37% metastatic tumors showed stronger cytoplasmic expression of MAC30 at the tumor invasive margins compared to inner tumor areas. Strong cytoplasmic expression of MAC30 in the metastasis was related to a poor prognosis (p = 0.04). MAC30 cytoplasmic expression was positively related to expression of proliferating cell nuclear antigen (p = 0.04), p53 (p = 0.04), nucleoporin 88 (p = 0.001), legumain (p = 0.004) and particularly interesting new cysteine-histidine rich protein (p = 0.004). However, MAC30 expression in the nucleus and stroma did not have any clinicopathological and biological significance (p > 0.05). In conclusion, MAC30 protein may play a role in development of colorectal cancer, and can be considered as a prognostic factor.
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| 39. |
- Murthy, RV, et al.
(author)
-
Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer
- 2005
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 11:6, s. 2293-2299
-
Journal article (peer-reviewed)abstract
- Purpose: Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed in several types of tumors including colorectal cancer. However, there is no study examining the relationship of legumain expression to clinocopatbologic and biological variables in colorectal cancers. Experimental Design: We investigated legumain expression in 164 primary colorectal cancers, 34 corresponding distant normal mucosa samples, 89 adjacent normal mucosa samples, and 33 lymph node metastases using immunohistochemistry. We also did Western blotting analysis on three additional colorectal cancers and three colonic cell lines. Results: Legumain expression was increased in primary tumors compared with distant or adjacent normal mucosa (P < 0.05), but there was no significant change between primary tumors and metastases (P > 0.05). Legumain expression was positively related to poorer differentiation/ mucinous carcinoma (P = 0.04), higher degree of necrosis (P = 0.03) and apoptosis (P < 0.0001), positive proliferating cell nuclear antigen (P < 0.0001) and p53 expression (P = 0.049), and had a positive tendency towards stromelysin 3 (P = 0.058) and PINCH positivity (P = 0.05). The patients with tumors that showed both weak and lower percentage of the legumain expression, either in tumor (P = 0.01) or in stroma (P = 0.04), had a better prognosis. Conclusions: The legumain expression may be involved in colorectal cancer development and have a prognostic value in the patients. ©2005 American Association for Cancer Research.
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| 40. |
- Pachkoria, Ketevan, et al.
(author)
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Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy
- 2005
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In: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 63:3, s. 739-744
-
Journal article (peer-reviewed)abstract
- Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p ≤ 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors. © 2005 Elsevier Inc.
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