Bolag Altan

MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation

MicroRNA-7 (miR-7) has been reported to be a tumor suppressor in all malignancies including colorectal cancer (CRC). However, its significance for CRC clinical outcomes has not yet been explored. The potential for miR-7 to act as a tumor suppressor by coordinately regulating the epidermal growth factor receptor (EGFR) signaling pathway at several levels was examined. We investigated the tumor inhibitory effect of miR-7 in CRC, with particular focus on the relationship between miR-7 and the EGFR pathway. Quantitative reverse transcription-PCR was used to evaluate miR-7 expression in 105 CRC cases to determine the clinicopathologic significance of this miRNA. The regulation of EGFR by miR-7 was examined with miR-7 precursor-transfected cells. Furthermore, we investigated whether miR-7 suppresses proliferation of CRC cells in combination with cetuximab, a monoclonal antibody against EGFR. Multivariate analysis indicated that low miR-7 expression was an independent prognostic factor for poor survival (P = 0.0430). In vitro assays showed that EGFR and RAF-1 are direct targets of miR-7, which potently suppressed the proliferation of CRC cells, and, interestingly, that the growth inhibitory effect of each of these was enhanced by cetuximab. miR-7 is a meaningful prognostic marker. Furthermore, these data indicate that miR-7 precursor, alone or in combination with cetuximab, may be useful in therapy against CRC.

Nuclear karyopherin-α2 expression in primary lesions and metastatic lymph nodes was associated with poor prognosis and progression in gastric cancer.

Karyopherin-α2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. We investigated the clinical and functional significance of KPNA2 in gastric cancer (GC). Immunohistochemistry was performed to examine KPNA2 expression in primary GC and metastatic lymph nodes. Next, KPNA2 was suppressed by small interfering RNA (siRNA) to examine KPNA2 function in proliferation and cisplatin-induced apoptosis of GC cell lines. Nuclear expression of KPNA2 in marginal regions of primary GC was stronger than in central regions of GC and normal tissues. The high expression of marginal KPNA2 was significantly associated with β-catenin accumulation in the nucleus and poor prognosis in two independent GC cohorts (discovery cohort, n = 90, P = 0.018; validation cohort, n = 89, P = 0.0125). We detected correlations between nuclear KPNA2 expression in marginal region and progression of macroscopic type (P = 0.036), tumor depth (P = 0.013), lymph node metastasis (P = 0.0064), venous invasion (P = 0.034) and clinical stage (P = 0.0006). Nuclear KPNA2 expression in marginal regions of metastatic lymph nodes was significantly higher than in the central region. It was associated with poor survival of GC patients with lymph node metastasis (n = 96; center, P = 0.4384; marginal, P < 0.0001). KPNA2 suppression enhanced cisplatin-induced apoptosis and reduced proliferation in the KPNA2 siRNA group compared with the control siRNA group. The expression of the DNA repair gene NBS1 (NBN) in the nucleus was suppressed in KPNA2-suppressed cells. KPNA2 might be a useful prognostic marker and an effective therapeutic target for GC.

FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I–specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. Implications: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. Visual Overview: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg. Mol Cancer Res; 12(1); 32–37. ©2013 AACR.

Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma

Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin‐dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high‐STMN1‐expression group were associated with shorter recurrence‐free survival and overall survival than those in the low‐expression group. An in vitro protein‐binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Forkhead box protein C2 contributes to invasion and metastasis of extrahepatic cholangiocarcinoma, resulting in a poor prognosis

Extrahepatic cholangiocarcinoma (EHCC) is a cancer with a poor prognosis, and the postoperative survival of patients depends on the existence of invasion and metastasis. The epithelial‐to‐mesenchymal transition (EMT) is an important step in EHCC invasion and metastasis. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported to induce the EMT. Therefore we examined the correlation between FOXC2 expression and clinical pathological factors, and analysed the function of FOXC2. The expression of FOXC2 in 77 EHCC cases was investigated by immunohistochemical staining, and the relationship between FOXC2 expression and clinicopathological factor was assessed. Knockdown by small interfering RNA (siRNA) was performed to determine the roles of FOXC2 in EHCC cell line. FOXC2 expression correlated with lymph node metastasis (P = 0.0205). Patients in the high FOXC2 expression group had a poorer prognosis than the patients in the low FOXC2 expression group. Moreover, FOXC2 knockdown inhibited cell motility and invasion, and decreased the expression of EMT markers (N‐cadherin, and matrix metalloproteinase (MMP) ‐2) and Angiopietin‐2 (Ang‐2). The EMT inducer FOXC2 contributes to a poor prognosis and cancer progression. FOXC2 may be a promising molecular target for regulating EHCC metastasis.

SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non‐small cell lung cancer

Despite advances in the development of various therapeutic agents, non‐small cell lung cancer (NSCLC) is associated with a poor prognosis. To improve the prognosis of patients with NSCLC, new therapeutic targets for overcoming drug resistance are required. The process of autophagy is required to support the tumorigenesis and drug resistance of cancer cells. We investigated the clinical significance of SIRT6, a member of the NAD+‐dependent deacetylase family, which regulates a variety of cancer‐related processes, including autophagy.

Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer

Heat shock protein (HSP) expression is induced by the exposure to stress, such as fever, oxidative stress, chemical exposure, and irradiation. In cancer, HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis. In colorectal cancer, a loss-of-function mutation of HSP110 (HSP110ΔE9) has been identified. HSP110ΔE9 inhibits the nuclear translocation of wild-type HSP110, which is important for its chaperone activity and anti-apoptotic effects. The patients carrying HSP110ΔE9 mutation exhibit high sensitivity to anticancer agents, such as oxaliplatin and 5-fluorouracil. There is still insufficient information about HSP110 localization, the clinicopathological significance of HSP110 expression, and its association with chemotherapy resistance in gastric cancer. Here, we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with cancer progression, poor prognosis, and recurrence after adjuvant chemotherapy. In vitro results showed that HSP110 suppression increases the sensitivity to 5-fluorouracil and cisplatin of human gastric cancer cell lines. Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for gastric cancer and a potential molecular therapeutic target for the treatment of gastric cancer patients with acquired anticancer drug resistance.

Blood group substances as potential therapeutic agents for the prevention and treatment of infection with noroviruses proving novel binding patterns in human tissues.

Blood group-related glycans determining ABO and Lewis blood groups are known to function as attachment factors for most of the norovirus (NoV) strains. To identify binding specificity of each NoV, recombinant norovirus-like particles (VLPs) and human saliva samples with different ABO, Lewis phenotypes and secretor status have been commonly applied. When binding specificities of VLPs prepared from 16 different genotypes of NoVs in GI and GII genogroups were characterized in samples of human gastric mucosa compared to human saliva based on blood group phenotypes, considerable differences were observed for several strains. Novel binding specificities determined by an ELISA using preparations from human gastric mucosa were also ascertained by immunohistochemical analyses using human jejunal mucosa, widely believed to be susceptible to NoV infection. Further, A, B and O(H) blood group substances prepared from porcine and squid tissues were found to be effective for preventing ABO blood group-specific binding of VLPs to both saliva and mucosa samples. Therefore, these blood group substances might have potential for the prevention and treatment of NoV infection.

High STMN1 level is associated with chemo-resistance and poor prognosis in gastric cancer patients

Background:Stathmin1 (STMN1) is a cytosolic phosphoprotein that regulates cellular microtubule dynamics and is known to have oncogenic activity. Despite several reports, its roles in gastric cancer (GC) remain unclear owing to a lack of analyses of highly metastatic cases. This study aimed to investigate STMN1 as a prognostic and predictive indicator of response to paclitaxel therapy in patients with GC, including inoperable cases.Methods:Immunohistochemical analysis of STMN1 was performed on both operable (n=95) and inoperable GC (n=61) samples. The roles of STMN1 in cancer cell proliferation and sensitivity to a microtubule-targeting drug, paclitaxel, were confirmed by knockdown experiments using GC cell lines.Results:Multivariate and Kaplan–Meier analyses demonstrated that high STMN1 was predictive of poor prognosis in both the groups. In the operable cohort, STMN1 expression correlated with cancer curability, recurrence, and resistance to adjuvant therapy. A correlation with paclitaxel resistance was observed in inoperable cases. Knockdown of STMN1 in GC cell lines inhibited proliferation and sensitised the cells to paclitaxel by enhancing apoptosis.Conclusions:STMN1 is a possible biomarker for paclitaxel sensitivity and poor prognosis in GC and could be a novel therapeutic target in metastatic GC.

Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma.

The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain‐related proteins A and B (MICA/B), unique long 16 binding protein (ULBP) 1, and ULBP2/5/6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA/B or ULBP2/5/6 correlated with overall and disease‐free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease‐free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease‐free survival than that observed with the overexpression of any one NKG2D ligand. Co‐expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co‐overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.