Colorectal cancer is one of the most common cancers and pancreatic cancer is among the most fatal and difficult to treat. New prognostic biomarkers are urgently needed to improve the treatment of colorectal and pancreatic cancer. Protein regulating cytokinesis 1 (PRC1), kinesin family member 14 (KIF14) and citron Rho-interacting serine/threonine kinase (CIT) serve important roles in cytokinesis, are strongly associated with cancer progression and have prognostic potential. The present study aimed to investigate the prognostic relevance of the PRC1, KIF14 and CIT genes in colorectal and pancreatic cancer. PRC1, KIF14 and CIT transcript expression was assessed by reverse transcription-quantitative PCR in tumors and paired distant unaffected mucosa from 67 patients with colorectal cancer and tumors and paired non-neoplastic control tissues from 48 patients with pancreatic cancer. The extent of transcript dysregulation between tumor and control tissues and between groups of patients divided by main clinical characteristics, namely patients' age and sex, disease stage, localization and grade, was determined. Finally, the associations of transcript levels in tumors with disease-free interval and overall survival time were evaluated. PRC1, KIF14 and CIT transcripts were upregulated in tumors compared with control tissues. PRC1, KIF14 and CIT levels strongly correlated to each other in both colorectal and pancreatic tumor and control tissues after correction for multiple testing. However, no significant associations were found among the transcript levels of PRC1, KIF14 and CIT and disease-free interval or overall survival time. In summary, the present study demonstrated mutual correlation of PRC1, KIF14 and CIT cytokinesis regulators with no clear prognostic value in pancreatic and colorectal cancers. Hence, according to the results of the present study, transcript levels of these genes cannot be clinically exploited as prognostic biomarkers in colorectal or pancreatic cancer patients.

• Keywords
• cancer, colon, cytokinesis, gene expression, pancreas, prognosis, rectum,
• Publication type
• Journal Article MeSH

The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.

• MeSH
• Albumins pharmacology   MeSH
• Deoxycytidine analogs & derivatives   pharmacology   MeSH
• Carcinoma, Pancreatic Ductal drug therapy   genetics   MeSH
• Gemcitabine MeSH
• Humans MeSH
• Mice, Nude MeSH
• Mice MeSH
• Biomarkers, Tumor genetics   MeSH
• Cell Line, Tumor MeSH
• Pancreatic Neoplasms drug therapy   genetics   MeSH
• Paclitaxel pharmacology   MeSH
• Bridged-Ring Compounds pharmacology   MeSH
• Cell Proliferation drug effects   genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Signal Transduction drug effects   genetics   MeSH
• Taxoids pharmacology   MeSH
• Transcriptome drug effects   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 130-nm albumin-bound paclitaxel MeSH Browser
• Albumins MeSH
• Deoxycytidine MeSH
• Gemcitabine MeSH
• KRAS protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Paclitaxel MeSH
• Bridged-Ring Compounds MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• taxane MeSH Browser
• Taxoids MeSH

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Κirsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene mutation analysis was performed using the KRAS/BRAF/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS-mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v-raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS-targeted therapies in PDAC.

• Keywords
• KRAS, gene expression, mutation, overall survival, pancreatic ductal adenocarcinoma,
• Publication type
• Journal Article MeSH

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo. Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.

• MeSH
• Carcinoma, Pancreatic Ductal drug therapy   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Mice, Nude MeSH
• Pancreatic Neoplasms drug therapy   genetics   MeSH
• Disease-Free Survival MeSH
• Hedgehog Proteins genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged MeSH
• Taxoids administration & dosage   therapeutic use   MeSH
• Transcriptome drug effects   MeSH
• Treatment Outcome MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• KRAS protein, human MeSH Browser
• Hedgehog Proteins MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• Taxoids MeSH