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Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.

ABSTRACT: BACKGROUND:Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT. METHODS:140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins. RESULTS:TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p?=?0.043, HR, 6.160, 95% CI, 1.063-35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3. CONCLUSIONS:Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.

SUBMITTER: Pathak S

PROVIDER: S-EPMC4032294 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.

Pathak Surajit S Meng Wen-Jian WJ Zhang Hong H Gnosa Sebastian S Nandy Suman Kumar SK Adell Gunnar G Holmlund Birgitta B Sun Xiao-Feng XF

PloS one 20140523 5

<h4>Background</h4>Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial o ...[more]

PMID: 24858921

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Project description:PurposeThe purpose of this study was to establish the influence of time interval between preoperative hyperfractionated radiotherapy (5 × 5 Gy) and surgery on long-term overall survival (5 years) and recurrence rate in patients with locally advanced rectal cancer operated on according to total mesorectal excision technique.MethodsThe treatment group comprised 154 patients with locally advanced rectal cancer who were operated on between 1999 and 2006 in the 1st Department of General Surgery, Jagiellonian University, Cracow, Poland. The data on survival has been systematically collected until 31st of December 2010. In addition, the following aspects were analyzed: the significance of time interval between the end of radiotherapy and surgical treatment and its influence on downsizing, downstaging, rate of curative resections, and sphincter-sparing procedures. Patients were qualified to preoperative radiotherapy 5 × 5 Gy and then randomly assigned to subgroups with different time intervals between radiotherapy and surgery: one subgroup consisted of 77 patients operated on 7-10 days after the end of irradiation, and the second subgroup consisted of 77 patients operated on after 4-5 weeks. Both groups were homogenous in sex, age, cancer stage and localization, distal and circumferential resection margins, and number of resected lymph nodes.ResultsThe 5-year survival rate in patients operated on 7-10 days after irradiation was 63%, whereas in those operated on after 4-5 weeks, it was 73%-the difference was not statistically significant (log rank, p = 0.24). A statistically significant increase in 5-year survival rate was observed only in patients with downstaging after radiotherapy-90% in comparison with 60% in patients without response to neoadjuvant treatment (log rank, p = 0.004). Recurrence was diagnosed in 13.2% of patients. A lower rate of systemic recurrence was observed in patients operated on 4-5 weeks after the end of irradiation (2.8% vs. 12.3% in the subgroup with a shorter interval, p = 0.035). No differences in local recurrence rates were observed in both subgroups of irradiated patients (p = 0.119). The longer time interval between radiotherapy and surgery resulted in higher downstaging rate (44.2% vs. 13% in patients with a shorter interval, p = 0.0001) although it did not increase the rate of sphincter-saving procedures (p = 0.627) and curative resections (p = 0.132).Conclusions1. Improved 5-year survival rate is observed only in patients with downstaging after preoperative irradiation dose of 25 Gy. 2. Longer time interval after preoperative radiotherapy 25 Gy does not improve the rate of sphincter-saving procedures and curative resections (R0) despite higher downstaging rate observed in this regimen.

Project description:Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on radiotherapy (RT) response and clinical outcome in rectal cancer patients remains unclear. In this study, we used real-time polymerase chain reaction to examine the expressions of miR-302a, miR-105, and miR-888 in normal mucosa and cancer tissue from rectal cancer patients with and without preoperative RT. The biological function of miR-302a, miR-105, and miR-888 expression was further analyzed and identified through the public databases: TCGA (The Cancer Genome Atlas) and GEPIA (Gene Expression Profiling Interactive Analysis). The results showed that the expression of miR-105 in rectal cancer was higher than that in normal mucosa in RT (P = 0.042) and non-RT patients (P = 0.003) and was associated with mucinous histological type (P = 0.004), COX-2 (P = 0.042), and p73 expression (P = 0.030). The expression of miR-302a was shown more frequently in cancers with necrosis (P = 0.033) and with WRAP53 expression (P = 0.015), whereas miR-888 expression occurred more frequently in tumors with protein the expression of survivin (P = 0.015), AEG-1 (astrocyte elevated gene-1) (P = 0.003), and SATB1 (special AT-rich sequence binding protein 1) (P = 0.036). Moreover, TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. The miRNA-gene network analysis showed that ABI2 was associated with all the three miRNAs, with lower expression and good diagnostic value in rectal cancers. The TCGA database demonstrated the association of miR-105 expression with high carcinoembryonic antigen level (P = 0.048). RT reduced the expressions of miR-302a, miR-105, and miR-888. Prognostic analysis showed that miR-888 expression was independently associated with worse survival of patients without RT [overall survival, P = 0.001; disease-free survival, P = 0.009]. Analysis of biological function revealed that the protein serine/threonine kinase activity and PI3K-AKT signaling pathway were the most significantly enriched functions and pathways, respectively. Our findings suggest that miR-105 is involved in rectal cancer pathogenesis and miR-888 is associated with prognosis. MiR-302a, miR-105, and miR-888 have potential influence on the pathogenesis, RT, and prognosis of rectal cancer.

Dataset Information

Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.

Publications

Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.

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