Rectal perforation following endorectal prostate MRI: an unexpected complication.

BACKGROUND: Prostate cancer is a common cancer among men in developed countries. Prostate magnetic resonance imaging (MRI) has been widely employed for early diagnosis of prostate cancer and recommending a treatment plan. The incidence of rectal perforation during endorectal prostate MRI is rare and has never been reported before. Herein, we present a case of rectal perforation after a prostate MRI examination that was subjected to emergency surgical intervention because of the acute presentation of generalized peritonitis. Patients with systemic comorbidities are reportedly at greater risks of encountering colonoscopic perforation. Endorectal prostate MRI is a safe diagnostic modality, but inadequate lubrication of the endorectal coil or over-insufflation of the balloon during the procedure may also lead to serious complications such as hollow organ perforation. Early surgery will be necessary should peritoneal symptoms persist. CASE PRESENTATION: In 2015, a 56-year-old man came to our ER due to acute abdominal pain after he finished his MRI exam. The exam indicated diffuse tenderness over his abdomen and at the ER, his abdominal CT (computerized tomography) was checked. The images revealed extraluminal air in the perirectal fat and the pneumoperitoneum. In response, exploratory laparotomy, simple closure of rectal perforation, and loop-S colostomy were performed and the patient was discharged 1 month after operation. CONCLUSIONS: Prostate MRI is a secure procedure with few complications. Clinicians must keep in mind the possibility of perforation when using ultrasound probe. Hollow organ perforation can result in serious morbidity or death. As a result, patients need to be informed of the complications of prostate MRI. When performing the procedure, clinicians must be cautioned about the potential problems for patients with high-anesthetic risk.

Simvastatin induces G1 arrest by up-regulating GSK3ß and down-regulating CDK4/cyclin D1 and CDK2/cyclin E1 in human primary colorectal cancer cells.

Simvastatin (SIM), a widely used cholesterol-lowering drug, also exhibits tumor-suppressive potentials in several types of malignancy. Colorectal cancer (CRC), the third most common malignant neoplasm, accounts for the second most leading cause of cancer-related deaths worldwide. In the present study, we investigated the anticancer effects of SIM on CRC using primary cancer cells lines (CPs: CP1 to CP5) isolated from five Taiwanese colorectal cancer patients as a model for colorectal cancer. We treated all five CPs with SIM for 24-72 hr and observed the respective cell viability by an MTT assay. SIM increased DNA content of the G1 phase, but did not induce apoptosis/necrosis in CPs as shown by flow cytometry with propidium iodide (PI)/annexin V double staining and PI staining. The expression of G1 phase-related proteins was analyzed by RT-PCR and Western blotting. SIM suppressed cell growth and induced cell cycle G1 -arrest by suppressing the expression of CDK4/cyclin D1 and CDK2/cyclin E1, but elevating the expression of glycogen synthase kinase 3ß in CPs. Our findings indicate that SIM may have antitumor activity in established colorectal cancer.

Successful reuse of a transplanted kidney 9 years after initial transplantation: 4-year follow-up.

BACKGROUND: Kidney transplantation is the preferred renal replacement therapy for patients with end-stage renal disease, but the waiting list for kidneys continues to grow because of a shortage of donor organs. The reuse of transplanted kidneys would seem to be a good approach to expand the pool of available organs. Here, we describe the reuse of a kidney 9 years after the initial transplantation. At 4-year follow-up, the second recipient is showing good renal function. CASE PRESENTATION: In 2005, a kidney was transplanted from a 40-year-old man, who suffered brain death due to an intracranial hemorrhage, into a 45-year-old man. Nine years later, the recipient suffered a ruptured cerebral aneurysm, resulting in brain death. The kidney was re-transplanted into a 40-year-old man with diabetic nephropathy who had received hemodialysis for 5 years. During 4 years of follow-up, the graft has functioned well. CONCLUSIONS: This case demonstrates the successful regrafting of a transplanted kidney. We believe this is the longest period for reuse of kidney after initial transplantation. The outcome suggests that a well-functioning transplanted kidney can be reused years after transplantation.

Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist-mediated CD10 expression.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially, in eastern Asia, and its prognosis is poor once metastasis occurs. Niclosamide, a US Food and Drug Administration-approved antihelmintic drug, was shown to inhibit the growth of various cancers including HCC, but the effect of niclosamide on cell motility and the underlying mechanism have not yet been completely defined. The present study demonstrated that niclosamide, at 0-40 nM, concentration-dependently inhibited wound closure and the migratory/invasive capacities of human Huh7 and SK-Hep-1 HCC cells without exhibiting cytotoxicity. A protease array analysis showed that CD10 was dramatically downregulated in Huh7 cells after niclosamide treatment. Western blot and flow cytometric assays further demonstrated that CD10 expression was concentration-dependently downregulated in Huh7 and SK-Hep-1 cells after niclosamide treatment. Mechanistic investigations found that niclosamide suppressed Twist-mediated CD10 transactivation. Moreover, knockdown of CD10 expression by CD10 small interfering RNA in HCC cells suppressed cell migratory/invasive abilities and overexpression of CD10 relieved the migration inhibition induced by niclosamide. Taken together, our results indicated that niclosamide could be a potential agent for inhibiting metastasis of HCC, and CD10 is an important target of niclosamide for suppressing the motility of HCC cells.

MiR-148a and miR-152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM.

Activated leukocyte cell adhesion molecule (ALCAM), also called CD166 is a 105-kDa transmembrane glycoprotein of the immunoglobin superfamily. In this study, we studied the association between ALCAM expression and tamoxifen resistance in ER + breast cancer and further investigated how ALCAM is regulated in the cancer cells. IHC staining data showed that the tumor tissues from non-responders (N = 20) generally had significantly stronger ALCAM staining than that from tamoxifen responders (N = 16). In vitro cell assay also confirmed ALCAM upregulation in tamoxifen resistant (TamR) MCF-7 cells than in tamoxifen sensitive (TamS) MCF-7 cells. ALCAM overexpression significantly alleviated 4-Hydroxytestosterone (4-OHT) induced cell viability inhibition and cell apoptosis in TamS MCF-7 cells, while ALCAM knockdown remarkably enhanced 4-OHT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. Demethylation reagent treatment significantly restored miR-148a and miR-152 expression in TamR MCF-7 cells. MiR-148a and miR-152 can directly target ALCAM 3'UTR and decrease ALCAM expression. MiR-148a overexpression had similar effect as ALCAM siRNA on enhancing 4-OHT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. MiR-152 overexpression alone caused growth inhibition and increased cell apoptosis in TamR MCF-7 cells. It also enhanced the effect of 4-OHT. Simultaneous inhibition of miR-148a and miR-152 significantly protected TamS MCF-7 cells from 4-OHT induced cell viability inhibition and cell apoptosis. Based on these findings, we infer that MiR-148a and miR-152 can sensitize TamR MCF-7 cells to tamoxifen at least via downregulating ALCAM.

Incidentally portal vein penetration during cannulation in endoscopic retrograde cholangiopancreatography: a case report.

Portal vein cannulation is a very rare complication of endoscopic retrograde cholangiopancreatography (ERCP). In most reported cases, the event was managed safely with immediate catheter, guidewire withdrawn and procedure termination. Here, we report an unusual case of portobiliary fistula created during ERCP. To our knowledge, this is the first report of such case managed with immediate surgical biliary exposure.

Association of diabetes mellitus with early-onset colorectal cancer: A systematic review and meta-analysis of 19 studies including 10 million individuals and 30,000 events.

BACKGROUND AND AIMS: Early-onset colorectal cancer (EoCRC) constitutes 2%-10% of all colorectal cancers and is becoming more common globally. Diabetes mellitus (DM) has increased substantially in younger adults; however, its involvement in EoCRC remains unclear. We conducted a systematic review and meta-analysis of observational studies to (1) explore the prevalence of DM in individuals with EoCRC and (2) investigate the association between DM and EoCRC. METHODS: A systematic literature search was conducted to identify studies published before May 2022 that evaluated the association between DM and EoCRC risk in four databases, including Medline (PubMed), Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Results from the studies were summarized in meta-analyses using random effects models. RESULTS: Nineteen eligible studies were included. A total of 33,359 EoCRC cases and 14,259,289 controls in 12 studies were included in the meta-analysis. The pooled odds ratio [OR] of 1.43 (95% confidence interval [CI]: 1.08-1.8) indicated significant positive association between DM and increased risk of EoCRC. Subgroup analysis demonstrated that diabetes severity was significantly associated with unmanaged DM (OR = 1.28, 95% CI: 1.02-1.6), but not with managed DM (OR = 1.04, 95% CI: 0.84-1.28). CONCLUSION: Our results suggest that DM is a risk factor for EoCRC, and the higher prevalence of DM among younger adults may contribute to the increasing incidence of EoCRC. Interventions to reduce this bidirectional risk should be further investigated for the development of effective prevention and treatment strategies. PROSPERO registration: CRD42022306347.

The promoting effect of adiponectin in hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Adipokines may explain the newly established association of obesity with hepatocellular carcinoma (HCC). This study investigated if adiponectin levels in HCC patients differed from healthy controls and their potential effect in the development of HCC. METHODS: Radioimmunoassay was used to determine serum adiponectin levels of 65 HCC patients and 165 healthy controls. The expressions of adiponectin protein in the tumor and adjacent non-tumor parts were examined by the immunoblotting method. Cell proliferation assays were used to assess the bioeffects of adiponectin in two human liver cancer cell lines. RESULTS: Serum adiponectin levels were significantly higher in the HCC patients than the controls. Significant correlations of serum adiponectin levels with serum triglyceride levels and insulin resistance were found in the controls, but not in the HCC patients. In contrast, serum adiponectin levels significantly correlated with serum albumin and alkaline phosphatase levels in the HCC patients, but this trend was not observed in the controls. The expression pattern of adiponectin protein between the paired tumor and adjacent non-tumor tissues significantly correlated with tumor size. In vitro, adiponectin increased cell proliferation in a dose-dependent manner. CONCLUSIONS: Increased adiponectin expressions were found in HCC and this increase might contribute to tumor growth.

In vitro biocompatibility of thermally gelling liquid mucoadhesive loaded curcuminoids in colorectal cancer chemoprevention.

PURPOSE: Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan; it ranks top three in the cancer mortality rate. Curcuminoids are derived from the rhizome of Curcuma longa. It has shown anti-cancer activity and apoptosis induction in a variety of cancer cell lines. This aims to study the potential of Poloxamer 407 as the thermogelling and mucoadhesive polymer for development of a site-targeting delivery system to enhance the localized delivery of curcuminoids to the colorectal cells for CRC chemotherapy. METHODS: The mucoadhesive strength and rheological properties were measured as a function of poloxamer loaded with curcuminoids. RESULTS: The gelation temperature of Poloxamer 407 was found to vary with its concentration and start gelling at 37°C at the concentration of 15.5% (w/v). To ensure gelation at physiological temperature after intra-rectal application, gelation temperature was determined by rheological measurement as well as by its physical appearance. The results indicated that its mucoadhesive strength also shows a dependency on temperature, which appears to be related to the increment in the maximum strength and average strength of the polymer. CONCLUSION: The results have suggested that Poloxamer 407 could be a potential thermogelling and mucoadhesive polymer for the development of a site-targeting colorectal drug delivery system for curcuminoids in colorectal cancer therapy.

A observational study of the efficacy and safety of capecitabine versus bolus infusional 5-fluorouracil in pre-operative chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: This study is to evaluate the safety and efficacy of preoperative radiotherapy (RT) combined with bolus infusional 5-fluorouracil (5-FU) or oral capecitabine in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Seventy-four patients were retrospectively analyzed. Twenty-seven patients were treated with 5-FU (350 mg/m(2) i.v. bolus) and leucovorin (20 mg/m(2) i.v. bolus) for 5 days/week during week 1 and 5 of RT. Forty-seven patients were treated with capecitabine (850 mg/m(2), twice daily for 5 days/week). Both groups received the same RT course (45-50.4 Gy/25 fractions, 5 days/week, for 5 weeks). Patients underwent surgery in 6 weeks after completion of the chemoradiotherapy. Data of the observational study were collected. RESULTS: Grade 3 or 4 toxicities occurred in 40.7% (5-FU) and 19.1% (capecitabine) of the patients (P = 0.044). Six patients in the 5-FU group (22.2%) and six patients in the capecitabine group (14%) achieved complete response. Primary tumor (T) downstaging were achieved in 51.9% (5-FU) and 69.8% (capecitabine) of the patients. The pathological ypT0-2 stage was 40.7% (5-FU) and 67.4% (capecitabine) (P = 0.028). CONCLUSIONS: In consideration of the better ypT0-2 downstaging rate, less severe toxicities, and no need for indwelling intravenous device on oral capecitabine regimen, the administration of oral capecitabine with RT may be a more favorable option in the neoadjuvant treatment for LARC.

Apoptosis Induction in Primary Human Colorectal Cancer Cell Lines and Retarded Tumor Growth in SCID Mice by Sulforaphane.

We have investigated the anticancer effects of the dietary isothiocyanate sulforaphane (SFN) on colorectal cancer (CRC), using primary cancer cells lines isolated from five Taiwanese colorectal cancer patients as the model for colorectal cancer. SFN-treated cells accumulated in metaphase (SFN 6.25 µM) and subG1 (SFN 12.5 and 25 µM) as determined by flow cytometry. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-3, and loss of mitochondrial membrane potential (ΔΨm). Incubations at higher SFN doses (12.5 and 25 µM) resulted in cleavage of procaspase-3 and elevated caspase-2, -3, -8, and -9 activity, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Daily SFN s.c. injections (400 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with primary human CRC (CP1 to CP5) s.c. tumors resulted in a decrease of mean tumor weight by 70% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have antitumor activity in established colorectal cancer.

Comparison of mini laparotomy with conventional laparotomy as the surgical approach in stage I-III CRC patients: appealing outcomes.

BACKGROUND/AIMS: Mini laparotomy is technical for the resection of colorectal cancer (CRC) in selected patients. The aim was to compare clinical outcomes of mini laparotomy with conventional laparotomy in CRC patients. METHODOLOGY: Between january 2007 and june 2010, 138 patients and 117 patients underwent elective resection using either mini laparotomy or conventional laparotomy respectively. Mini laparotomy involved a colorectal resection performed through a skin incision ≤8 cm in length. Clinicopathological factors, operative procedure and postoperative course were retrospectively analyzed to compare clinical outcomes between the two groups. RESULTS: Mini laparotomy seems to be an attractive alternative for resection of CRC in selected patients. Clinicopathological and histopathological features were similar between both groups, whereas intraoperative blood loss, operative time and harvested lymph-node numbers in conventional laparotomy were significantly greater (p=0.003, p=0.008 and p=0.024, respectively). Postoperative relapse, complications and hospitalization were significantly better in the mini laparotomy (all p<0.001). In comparison of postoperative complications between convention and mini laparotomy, ileus was more frequently encountered in conventional group (p=0.001). Interestingly, the disease-free survival and overall survival in mini laparotomy group were significantly better than control group (p=0.001 and p=0.017, respectively). CONCLUSIONS: Compared to conventional laparotomy, mini laparotomy seems a feasible, minimally invasive and attractive alternative in selected patients.

The effect of postoperative hyperbaric oxygen treatment on intra-abdominal adhesions in rats.

Abdominal adhesions, whether caused by peritoneal trauma, radiation, infection, or a congenital condition, are associated with a wide range of complications. These complications include chronic abdominal or pelvic pain, infertility, and adhesive small bowel obstruction. Such adhesions render re-operation difficult, with attendant risks of inadvertent enterostomy and increased operation time. The purpose of this study was to investigate the potential of hyperbaric oxygen (HBO) therapy in the prevention of abdominal adhesions in an experimental animal study. A laparotomy was performed on Wistar rats to induce the formation of adhesions on the cecum and the intra-abdominal area (1 ´ 2 cm). A superficial layer of the underlying muscle from the right abdominal wall was also shaved and prepared for aseptic surgery. The rats were divided into four groups according to the duration of HBO therapy; five additional groups were designated according to the conditions of HBO therapy. When the rats were evaluated according to adhesion area and grade, a statistically significant difference was observed between the control and HBO treatment groups (p < 0.005). Results from this study suggest that HBO treatment could reduce adhesion formation; and further suggest that HBO therapy may have therapeutic potential in the treatment of postoperative peritoneal adhesion.

PD-L1 expressed from tumor cells promotes tumor growth and invasion in lung cancer via modulating TGF-ß1/SMAD4 expression.

BACKGROUND: Programmed death ligand-1 (PD-L1) has a known association with the prognosis of human cancers because of its ability to alter tumor immune surveillance via its interaction with PD-1. We questioned whether expression of PD-L1 in tumor cells could directly promote tumor growth and invasiveness in non-small cell lung cancer (NSCLC). METHODS: Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate PD-L1 messenger RNA (mRNA) expression in lung tumors. The prognostic value of PD-L1 mRNA was assessed by Cox regression model. Transcriptional regulation of PD-L1 by human papillomavirus (HPV) 16/18 E6 oncoprotein or by epidermal growth factor receptor (EGFR) mutation in lung cancer cells was examined by Western blot and luciferase reporter assay. The cell growth and invasion were evaluated by colony formation, soft agar growth, and Boyden chamber assay. RESULTS: The PD-L1 mRNA levels showed a positive association with HPV 16/18 E6 oncoprotein and with EGFR mutation in 223 surgically resected NSCLC patients. The prognostic significance of PD-L1 was more commonly observed in patients with high PD-L1/E6 positive and high PD-L1/EGFR mutant tumors. Mechanistically, upregulation of PD-L1 transcription by E6 or mutant EGFR occurred largely through the ERK-C/EBPß-TLR4-NF-κB cascade. PD-L1 promotes the efficacy of colony formation, soft agar growth, and cell invasion. PD-L1 upregulates BAG-1 to reduce transforming growth factor (TGF)-ß1 expression, and the decrease in SMAD4 because of TGF-ß1 occurs through the p53/microRNA (miR)-224 axis. The decreases in TGF-ß1 and SMAD4 are responsible for PD-L1-mediated cell invasiveness. CONCLUSION: Induction of PD-L1 by E6 oncoprotein or mutant EGFR through the ERK-C/EBPß-TLR4-NF-κB cascade may promote tumor growth and invasiveness in NSCLC because of decreasing TGF-ß1 and SMAD4 expression.

Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy.

OBJECTIVES: The objective of the study is to investigate whether multiple chemotherapeutic agent-related genetic polymorphisms are associated with the clinical outcomes of Taiwanese metastatic colorectal cancers (mCRC) patients treated with the first-line FOLFOX-4 chemotherapy. METHODS: Consecutive mCRC patients were prospectively enrolled into this study. Peripheral blood samples were used for genotyping of polymorphisms in MTHFR, DPD, GSTP1, MDR1, TYMS, ERCC1, XRCC1, and ERCC2 genes by polymerase chain reaction-restriction fragment length polymorphism technique and DNA sequencing. The primary end point of the study was to investigate the association of each genetic polymorphism with progression-free survival and overall survival (OS). RESULTS: Favorable genotypes from polymorphisms in ERCC1 codon 118C/C [hazard ratio (HR)=0.061, 95% confidence interval (CI): 0.014-0.274, P<0.001] and XRCC1 codon 399G/G (HR=0.306, 95% CI: 0.103-0.905, P=0.032) that are associated with progression-free survival were identified. Furthermore, ERCC1 codon 118C/C (HR=0.065, 95% CI: 0.011-0.377, P=0.002) and XRCC1 codon 399G/G (HR=0.152, 95% CI: 0.041-0.568, P=0.005) were significantly associated with favorable OS. Combining ERCC1 and XRCC1 genetic polymorphisms, patients with both favorable genotypes of ERCC1 codon 118C/C and XRCC1 codon 399G/G were associated with the better OS than those with one or without any favorable genotypes (P<0.001). CONCLUSION: The genetic polymorphisms of ERCC1 and XRCC1 may be useful in predicting clinical outcome in Taiwanese mCRC patients treated with FOLFOX-4. However, further prospective studies will be needed for the potential clinical implication.

Association of hOGG1-Cys variants with occurrence of p53 and EGFR deletion mutations in non-small cell lung cancer.

BACKGROUND: The human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene encodes a DNA glycosylase that removes 8-hydroxy-2-deoxyguanine (8-OH-dG) DNA damage to protect against gene mutations. The association of hOGG1 Ser326Cys polymorphism with lung cancer risk has predicted that hOGG1-Cys variants are less effective at removing 8-OH-dG damage from DNA; therefore, these variants might show an increased occurrence of tumor suppressor gene and oncogene mutations. However, no evidence has yet supported this hypothesis. METHODS: Direct sequencing was performed to examine the mutations of p53 and EGFR genes in lung tumors from patients with non-small cell lung cancer (NSCLC). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine hOGG1 Ser326Cys polymorphism in this study population. RESULTS: A total of 99 p53-mutated and 99 EGFR-mutated patients with NSCLC were selected to explore the possible associations of these mutations with hOGG1 Ser326Cys polymorphism. The p53-mutated and EGFR-mutated patients were divided into nondeletion and deletion subgroups. P53 deletion mutations were more commonly observed in male than in female patients (P = 0.030). However, EGFR exon 19 deletion mutations were more prevalent in female and adenocarcinoma patients than in male and squamous cell carcinoma patients (P = 0.028 for genders, P = 0.017 for tumor histology). Interestingly, p53 and EGFR exon 19 deletion mutations were more frequent in patients with hOGG1 Ser/Cys + Cys/Cys hOGG1-Cys variants than with the hOGG1 Ser/Ser genotype (P = 0.010 for p53, P = 0.032 for EGFR). CONCLUSIONS: We suggest that the association of hOGG1 Ser326Cys polymorphism with lung cancer risk could be partially explained by increases in p53 and EGFR deletion mutations. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: NSCLC patients with hOGG1-Cys variants may have a higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. WHAT THIS STUDY ADDS: NSCLC patients with hOGG1-Cys variants might be helpful to predict patients having higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib or erlotinib could be a higher risk to occur EGFR T790M mutation.

Intraperitoneal migration of a mesh plug with a small intestinal perforation: report of a case.

Tension-free hernia repair with a mesh plug shows a low recurrence rate, but in a very few cases it can result in new complications including mesh migration and violation of the peritoneum. This report describes the case of a 79-year-old man who had undergone an inguinal hernioplasty using a polypropylene mesh plug 2 years earlier. He had a laparotomy for bowel ischemia 18 months later, and no evidence of bowel adhesion or a plug protruding through the peritoneum at that time. The patient remained asymptomatic until this admission. He presented with acute abdomen, and an emergency laparotomy revealed a plug-related bowel perforation. The plug had migrated and penetrated the peritoneum, presenting with bowel perforation and adhesions. Although the etiology was not clear, the use of nonabsorbable sutures for plug fixation may be recommended to avoid this complication. Less than 10 cases of mesh migration with bowel complications have been reported, and this is the first case study to demonstrate migration of the plug by serial tomography.

Author Correction: PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via ß-catenin-mediated stemness.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cisplatin sensitivity mediated by NKX2-1 in lung adenocarcinoma is dependent on p53 mutational status via modulating TNFSF10 expression.

NKX2-1 was shown to enhance cisplatin sensitivity in KRAS-mutated cells, but it conferred cisplatin resistance in EGFR-mutated lung adenocarcinoma cells. However, NKX2-1 as a dual role in tumor progression depended on p53 mutational status via modulation of the NF-κB pathway. We hypothesized that NKX2-1 may confer cisplatin resistance in p53-mutated (p53-MT) lung adenocarcinoma cells but may enhance cisplatin sensitivity in wild-type (p53-WT) cells. In the present study, six p53-MT and -p53-WT cell lines were treated with various concentrations of cisplatin to calculate the inhibitory concentration of cisplatin for 50% cell viability (IC50). The IC50 value was positively correlated with NKX2-1 expression in the p53-MT cells but negatively correlated in the p53-WT cells. TNFSF10 was identified in a microarray analysis as a potential candidate responsible for NKX2-1-mediated apoptosis induced by cisplatin. The retrospective study evaluated 97 surgically resected lung adenocarcinoma patients receiving cisplatin-based chemotherapy to explore the possible association between NKX2-1 expression and tumor response. Patients with higher TNFSF10 mRNA levels, as determined by real-time reverse transcription-polymerase Chain Reaction (RT-PCR), typically showed an favorable response when compared with patients with lower TNFSF10 mRNA levels. Additionally, the association of higher TNFSF10 mRNA levels with favorable response was only revealed in p53-WT patients, not in p53-MT patients. Higher NKX2-1 mRNA levels were associated with an unfavorable response in patients with p53-MT tumors but a favorable response in patients with p53-WT tumors. In summary, modulation of TNFSF10 expression by NKX2-1 may be a potential indicator for predicting the response to cisplatin-based chemotherapy in patients with lung adenocarcinomas.

Hepatitis B virus X protein promotes tumor invasion and poor prognosis in hepatocellular carcinoma via phosphorylation of paxillin at Serine 178 by activation of the c-Jun NH2-terminal kinase.

Hepatitis B virus X protein (HBx) plays critical roles in hepatocellular tumorigenesis by activating different signaling pathways, including the c-Jun NH2-terminal kinase (JNK) pathway. Phosphorylation of paxillin (PXN) promotes cell migration via activation of the JNK signaling pathway, but PXN overexpression is not associated with poor outcome in patients with hepatocellular carcinoma (HCC). HBx gene manipulation and Western blotting indicated that phosphorylation of PXN at Serine 178 (pS178-PXN) by HBx may promote invasiveness in HCC cells via HBx-mediated JNK activation. Immunohistochemical analysis indicated a positive correlation between pS178-PXN and HBx expression levels in tumor specimens. The overall survival (OS) and relapse-free survival (RFS) were poorer in patients with high-pS178-PXN expressing or high-HBx expressing tumors than in patients with low-pS178-PXN expressing or low-HBx expressing tumors. In conclusion, phosphorylation of PXN at Serine 178 by HBx-mediated JNK activation may therefore play a critical role in tumor invasiveness and poor prognosis in patients with HBV-infected hepatocellular tumors. The expression levels of pS178-PXN may be a reliable prognostic biomarker to predict the clinical outcomes in patients with HBV-associated HCC.