The diagnostic and prognostic role of miR-27a in cancer.

MicroRNA-27a (miR-27a) has been reported to be abnormally expressed in patients with cancer, and it could play potential roles as a diagnostic and prognostic biomarker of cancers. However, the diagnostic and prognostic role remains unclear. Hence, this meta-analysis, based on published data, was conducted to assess the utility of miR-27a as a diagnostic and prognostic marker in various cancers. To identify eligible studies, databases: Web of Science, PubMed, and CNKI were searched, with 868 literatures obtained, 16 of which were included in the Meta-analysis. The pooled results of studies conducted with serum/plasma showed that miR-27a was a valuable diagnostic biomarker in cancers (area under curve (AUC)= 0.91, sensitivity (SEN)= 0.84, specificity (SPE)= 0.85), with the diagnostic value slightly reduced in tumor tissue samples (AUC=0.83, SEN=0.78, SPE: 0.74). Additionally, the pooled results revealed that high expression of miR-27a predicted poor prognosis of cancer in serum/plasma (hazard ratio (HR) = 0.63, PHeterogeneity = 0.278, I2= 21.50%) but not in tumor tissue (HR = 0.98, PHeterogeneity =0.577, I2= 0.0). In brief, our results suggested that miR-27a in serum/plasma or tumor tissue could act as a diagnostic biomarker, and that miR-27a in serum/plasma could predict cancer patients' survival.

A Case of Solitary Peutz-Jeghers Syndrome Leading to Chronic Small Bowel Obstruction Due to Intussusception From a Large Hamartomatous Polyp.

We report a case of a 33-year-old male who presented to the emergency department with a three-day history of severe diffuse abdominal pain associated with anorexia, nausea, and vomiting. Computed tomography (CT) imaging of the abdomen and pelvis revealed a long segment of intussusception in the proximal jejunum and a round lesion along the intussusception with punctate hyperdensities. The patient underwent a diagnostic laparoscopy converted to open small bowel resection and end-to-end anastomosis that demonstrated a pedunculated jejunal mass. The mass was removed, and the pathology revealed a hamartomatous polyp with features of Peutz-Jeghers syndrome (PJS). The patient did not have a family history, previous endoscopic findings, or physical exam findings such as mucocutaneous pigmentation that could be attributed to PJS.  Definitive diagnosis of solitary PJS-type hamartomatous polyps depends on histopathological findings. Genetic analysis for mutations of the PJS susceptible gene, STK11/LB1 located at 19p13.3, as well as loss of heterozygosity at that locus, have been used for the diagnosis of PJS. In patients with large pedunculated hamartomatous polyps, chronic intussusception can occur. If pathology reveals features of Peutz-Jeghers, but the patient lacks the characteristic mucocutaneous pigmentation, family history of PJS, or additional polyps within the GI tract, then solitary PJS may be suspected.

The Diagnostic and Prognostic Value of miR-155 in Cancers: An Updated Meta-analysis.

BACKGROUND: MicroRNA-155 has been discussed as a biomarker in cancer diagnosis and prognosis. Although relevant studies have been published, the role of microRNA-155 remains uncertain because of insufficient data. METHODS: We conducted a literature search in PubMed, Embase, and Web of Science databases to obtain relevant articles and extract data to evaluate the role of microRNA-155 in cancer diagnosis and prognosis. RESULTS: The pooled results showed that microRNA-155 presented a remarkable diagnostic value in cancers (area under the curve = 0.90, 95% confidence interval (CI 0.87-0.92; sensitivity = 0.83, 95% CI 0.79-0.87; specificity = 0.83, 95% CI 0.80-0.86), which was maintained in the subgroups stratified by ethnicity (Asian and Caucasian), cancer types (breast cancer, lung cancer, hepatocellular carcinoma, leukemia, and pancreatic ductal adenocarcinoma), sample types (plasma, serum, tissue), and sample size (n >100 and n <100). In prognosis, a combined hazard ratio (HR) showed that microRNA-155 was significantly associated with poor overall survival (HR = 1.38, 95% CI 1.25-1.54) and recurrence-free survival (HR = 2.13, 95% CI 1.65-2.76), and was boundary significant with poor progression-free survival (HR = 1.20, 95% CI 1.00-1.44), but not significant with disease-free survival (HR = 1.14, 95% CI 0.70-1.85). Subgroup analyses in overall survival showed that microRNA-155 was associated with poor overall survival in the subgroups stratified by ethnicity and sample size. However, the significant association was maintained in cancer types subgroups of leukemia, lung cancer, and oral squamous cell carcinoma, but not in colorectal cancer, hepatocellular carcinoma, and breast cancer, and was maintained in sample types subgroups of bone marrow and tissue, but not in plasma and serum. CONCLUSIONS: Results from this meta-analysis demonstrated that microRNA-155 was a valuable biomarker in cancer diagnosis and prognosis.

Small Bowel Follow-Through: Treatment for Small Bowel Obstruction or Delaying the Inevitable?

BACKGROUND: Over 400,000 patients are admitted annually for small bowel obstruction (SBO), of which 20-40% require operative intervention, representing more than 2.3 billion dollars in healthcare expenses. Recurrence of SBO increases with a longer duration of follow-up with up to 15-20% recurrence rates within a five-year period. Small bowel follow-through (SBFT) consisting of serial X-rays with oral contrast has been shown to decrease overall length of stay (LOS) in patients with adhesive SBO. The aim of this study is to determine if SBFT administered to patients with SBO decreases 30-day and up to five-year readmission rates secondary to recurrent SBO. METHODS: The institutional review board (IRB) approved a single institution retrospective study from 2010 to 2020 that included a total of 742 patients. These patients were organized into groups of those who received the SBFT <24 hours after admission (n=40), those who received the SBFT >24 hours (n=198), and the third group of patients who did not receive the SBFT (n=658). Readmission rates <30 days, 70 years along with BMI <25, 25-29.9, 30-34.9, 35-39.9, >40, as well as the number of intraabdominal surgeries, gender, and need for operative intervention during the admission were evaluated to assess for any associations with recurrence. Readmission within 30 days and up to five years were compared. RESULTS: There were no significant differences in recurrence rates between groups with SBFT <24 hours (p=0.338) or SBFT >24 hours (p=0.889) when compared to the no SBFT group. There was nearly a 48% chance of readmission for another episode of an SBO for patients who did not undergo an operative intervention. While patients who underwent operative intervention had around a 29% chance of having a subsequent episode of an SBO. This is consistent with a statistically significant decrease in one-year (p=0.027) recurrences in patients who underwent operative intervention. CONCLUSION: There was no significant difference in recurrences with gender, most BMI groups, or in groups who underwent an SBFT. Operative intervention is associated with a statistically significant decrease in recurrence rates of SBO within one year of presentation.

The diagnostic and prognostic value of the miR-17-92 cluster in hepatocellular carcinoma: A meta-analysis.

Previous studies demonstrated that microRNAs (miRNAs) could serve as biomarkers in various cancers. This meta-analysis aimed to determine the roles of a miR-17-92 cluster in hepatocellular carcinoma (HCC). Here, eligible included studies were searched through PubMed, Embase, and Wan Fang databases up to 1st February 2022. Relevant data were extracted from each eligible study to evaluate the relationship between miRNA-17-92 cluster miRNA expression and the diagnosis and prognosis of HCC. Finally, a total of 21 studies were pooled and included in the meta-analysis, of which four articles were used for diagnostic meta-analysis and eight articles were used for prognostic meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratios (DOR) of the miR17-92 cluster for diagnosis of HCC were 0.75 [95% confidence interval (CI): 0.64-0.83], 0.73 (95% CI: 0.65-0.79), and 7.87 (95% CI: 5.36-11.54), respectively. Also, the area under the curve (AUC) for the miR-17-92 cluster when diagnosing HCC was 0.79 (95% CI: 0.76-0.83). For prognostic analysis, hazard ratios (HRs) with 95% CIs were extracted from the included studies and pooled HRs were determined to assess the associations. Patients with increased expression of miR17-92 cluster miRNA were associated with poor overall survival (OS) and recurrence-free survival (RFS) (HR=1.86, 95% CI: 1.04-3.33; HR = 4.18, 95% CI: 3.02-5.77, respectively), but not progression-free survival (PFS) (HR = 0.43, 95% CI: 0.25-0.73), while no association of the miR-17-92 cluster high-expression was detected with disease-free survival (DFS) (HR: 0.95, 95% CI: 0.21-4.34). In short, current pieces of evidence suggested that the miR-17-92 cluster may serve as a novel diagnostic and prognostic biomarker for HCC. However, given the limited study number, larger-size, multi-center, and higher-quality studies are indispensable in the future.

Comparison between core needle biopsy and excisional biopsy for breast neoplasm.

ABSTRACT: This study aimed to explore clinical significance of core needle biopsy (CNB) in pathological diagnosis of breast neoplasm.Seventy one breast neoplasm samples were obtained from Tongzhou Maternal and Child Health Hospital of Beijing between the years of 2006 and 2014. Forty five specimens were obtained via CNB and cases offering 26 of them received neoadjuvant chemotherapy. Pathology, histology, and immunohistochemistry results were compared between CNB specimens and excisional biopsy.Upward and downward tendencies could be observed in CNB specimens and excisional biopsy, respectively, in all items. Tumor proportion of CNB tissues was (33 + 2)/45 = 77.78%, when ductal carcinoma in situ detected by both CNB and excisional biopsy was 31/45 = 68.89%, with a consistency of (31 + 3)/45 = 75.56%. Tumor thrombus detected by both CNB and excisional biopsy was 2/45 = 4.44%. Among cases receiving neoadjuvant chemotherapy, CNB and excisional biopsy, in mitotic figure, cytological scoring and histological grading, showed a total change rate of >50% (50%-75%), while changes in duct and cellular heteromorphism were not distinct. Cases showing changes were up to 73.08%, with 8/26 = 30.77% for rise and 11/26 = 42.31% for descent.CNB could be used for preoperative diagnosis of breast neoplasm, and help to determine proper treatment regimen, thus elevating the rate of breast conserving. However, this method still has several limitations, particularly in immunohistochemical tests of human epidermal receptor protein-2. Neoadjuvant chemotherapy may influence the accuracy of CNB diagnosis.

Single-Cell-Derived Primary Rectal Carcinoma Cell Lines Reflect Intratumor Heterogeneity Associated with Treatment Response.

PURPOSE: The standard treatment of patients with locally advanced rectal cancer consists of preoperative chemoradiotherapy (CRT) followed by surgery. However, the response of individual tumors to CRT is extremely diverse, presenting a clinical dilemma. This broad variability in treatment response is likely attributable to intratumor heterogeneity (ITH). EXPERIMENTAL DESIGN: We addressed the impact of ITH on response to CRT by establishing single-cell-derived cell lines (SCDCL) from a treatment-naïve rectal cancer biopsy after xenografting. RESULTS: Individual SCDCLs derived from the same tumor responded profoundly different to CRT in vitro. Clonal reconstruction of the tumor and derived cell lines based on whole-exome sequencing revealed nine separate clusters with distinct proportions in the SCDCLs. Missense mutations in SV2A and ZWINT were clonal in the resistant SCDCL, but not detected in the sensitive SCDCL. Single-cell genetic analysis by multiplex FISH revealed the expansion of a clone with a loss of PIK3CA in the resistant SCDCL. Gene expression profiling by tRNA-sequencing identified the activation of the Wnt, Akt, and Hedgehog signaling pathways in the resistant SCDCLs. Wnt pathway activation in the resistant SCDCLs was confirmed using a reporter assay. CONCLUSIONS: Our model system of patient-derived SCDCLs provides evidence for the critical role of ITH for treatment response in patients with rectal cancer and shows that distinct genetic aberration profiles are associated with treatment response. We identified specific pathways as the molecular basis of treatment response of individual clones, which could be targeted in resistant subclones of a heterogenous tumor.

A Case of Primary Melanoma of the Transverse Colon.

Melanoma is among the most prevalent neoplasms diagnosed annually with the vast majority arising from a cutaneous origin. Though there are described metastases to the gastrointestinal tract, there are only rare descriptions of primary gastrointestinal melanoma. Both diagnosis and management of this unique population can be challenging given the infrequency with which it occurs. To follow is the third reported case of transverse colon primary melanoma with a description of multimodality treatment with surgery, chemotherapy, and immunotherapy.

Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages.

Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflammatory cytokines, such as interleukin-1 beta (IL-1ß), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1ß following M. bovis infection are poorly understood. Here we show that the 'nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein' (NLRP7) inflammasome is involved in IL-1ß secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (C-C motif) ligand 3 (CCL3) and IL-1ß mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1ß secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages.

Inflammasomes-dependent regulation of IL-1ß secretion induced by the virulent Mycobacterium bovis Beijing strain in THP-1 macrophages.

Mycobacterium bovis is the causative agent of tuberculosis in cattle. Infection of macrophages with M. bovis leads to the activation of the "nucleotide binding and oligomerization, leucine-rich repeat and pyrin domains-containing protein 3" (NLRP3) and "absent in melanoma 2" (AIM2) inflammasomes, which in turn triggers release of the proinflammatory cytokine interleukin-1ß (IL-1ß) that contributes to bacterial clearance and plays a crucial role in the host defense. However, NLRP3 and AIM2 inflammasome activation is influenced by several factors and how IL-1ß secretion by M. bovis-infected macrophages is regulated via the inflammasome pathway remains unclear. Here we found that IL-1ß secretion and pro-IL-1ß protein accumulation were inhibited in THP-1 macrophages upon exposure to the virulent M. bovis Beijing strain in the presence of high K(+) concentrations, cycloheximide (a protein synthesis inhibitor) and PR-619 (a deubiquitinating enzyme inhibitor). Scavenging reactive oxygen species (ROS) induced by N-acetylcysteine reduced IL-1ß release independent of the mitochondrial permeability transition. Collectively, our results suggest that IL-1ß secretion by M. bovis-infected THP-1 macrophages is reduced by high extracellular K(+) concentration, inhibition of new protein synthesis, deubiquitination, and ROS generation.

C-Abl tyrosine kinase mediates neurotoxic prion peptide-induced neuronal apoptosis via regulating mitochondrial homeostasis.

Prion diseases are neurodegenerative disorders characterized by the accumulation of a disease-associated prion protein and apoptotic neuronal death. Previous studies indicated that the ubiquitous expression of c-Abl tyrosine kinase transduces a variety of extrinsic and intrinsic cellular signals. In this study, we demonstrated that a synthetic neurotoxic prion fragment (PrP106-126) activated c-Abl tyrosine kinase, which in turn triggered the upregulation of MST1 and BIM, suggesting the activation of the c-Abl-BIM signaling pathway. The peptide fragment was found to result in cell death via mitochondrial dysfunction in neuron cultures. Knockdown of c-Abl using small interfering RNA protected neuronal cells from PrP106-126-induced mitochondrial dysfunction, production of reactive oxygen species, and apoptotic events inducing translocation of Bax to the mitochondria, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3. Blocking the c-Abl tyrosine kinase also prevented neuronal cells from PrP106-126-induced apoptotic morphological changes. This is the first study reporting that c-Abl tyrosine kinase as a novel upstream activator of MST1 and BIM plays an important role in prion-induced neuron apoptosis via mitochondrial dysfunction. Our findings suggest that c-Abl tyrosine kinase is a potential therapeutic target for prion disease.

Hemagglutinating virus of Japan envelope (HVJ-E) can enhance the immune responses of swine immunized with killed PRRSV vaccine.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically detrimental pig pathogen that causes significant losses for the pig industry. The immunostimulatory effects of hemagglutinating virus of Japan envelope (HVJ-E) in cancer therapy and the adjuvant efficacy of HVJ-E have been previously evaluated. The objective of this study was to investigate the adjuvant effects of HVJ-E on immunization with killed PRRSV vaccine, and to evaluate the protective effects of this immunization strategy against virulent PRRSV infection in piglets. Next, the PRRSV-specific antibody response, lymphocyte proliferation, PRRSV-specific IL-2, IL-10 and IFN-γ production, and the overall protection efficacy were evaluated to assess the immune responses of the piglets. The results showed that the piglets inoculated simultaneously with killed PRRSV vaccine and HVJ-E had a significantly stronger immune response than those inoculated with killed PRRSV vaccine alone. Our results suggest that HVJ-E could be employed as an effective adjuvant to enhance the humoral and cellular responses of piglets to PRRSV.

Cellular prion protein released on exosomes from macrophages binds to Hsp70.

Prion diseases are infectious and fatal neurodegenerative disorders. The cellular prion protein (PrP(C)) converting into misfolded isoform of prion protein (PrP(Sc)) is responsible for prion disease infection. Immune system plays an important role in facilitating the spread of prion infections from the periphery to the central nervous system. Macrophages were considered associated with the transportation and replication of PrP(Sc). So, understanding the PrP(C) trafficking in macrophages is important to explore the transport mechanism for PrP(Sc). Here, we isolated exosomes from the culture medium of Ana-1 macrophage cell line and investigated the PrP(C) trafficked by exosomes and the interaction of PrP(C) with Hsp70 in secreted exosomes by western blotting, immunoelectron microscopy, and co-immunoprecipitation. The results showed that the isolated vesicles from the culture medium of macrophages were characterized by exosomes and bore PrP(C). And PrP(C) bound to Hsp70 both in intracellular environment and secreted exosomes. In contrast, PrP(C) had no interaction with marker proteins of exosomes, Tag101 and Flotillin-1. These results suggested that PrP(C) present in extracellular space might be externalized through secreted exosomes from macrophages, and Hsp70 may play roles in the process of PrP(C) released via secreted exosomes.

Preventive effects of bexarotene and budesonide in a genetically engineered mouse model of small cell lung cancer.

In the present study, we examined the effect of bexarotene (Targretin) and budesonide in the chemoprevention of small cell lung carcinoma using a lung-specific knockout model of Rb1 and p53. Upon treatment with bexarotene, tumor incidence, number, and load were significantly reduced (P < 0.05). Budesonide treatment trended to inhibition, but the effect was not statistically significant (P > 0.05). Immunohistochemical staining indicated that bexarotene treatment decreased cell proliferation and increased apoptosis in tumors. The Rb1/p53 gene-targeted mouse seems to be a valuable model for chemopreventive studies on human small cell lung cancer. Our results indicate that the retinoid X receptor agonist bexarotene may be a potent chemopreventive agent in this cancer type.

Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs.

Antitumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers. We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (magnetic resonance imaging and computed tomography). ATB decreased lung SCC significantly (3.1-fold; P < 0.05) and increased lung hyperplastic lesions by 2.4-fold (P < 0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung. These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung SCCs.

Induction of macrophage migration by neurotoxic prion protein fragment.

Prion diseases are characterized by accumulation of protease resistant isoforms of prion protein (PrP), and infiltration and activation of mononuclear phagocytes at the brain lesions. Interactions between prion proteins and immune cells during disease progression are still not very well understood. In the present study, multiwell chamber chemotaxis assay was carried out to assess the migratory response of macrophage cell line Ana-1 to a synthetic peptide homologous to residues 106-126 of the human prion protein. Specific protein kinase inhibitors were used to elucidate the signaling events underlying PrP106-126-induced macrophages migration, and a comparison with the signaling pattern of macrophage migration induced by substance P (SP) and N-formyl-methionyl-leucyl-phenylalanine (fMLP), respectively, was carried out. The results showed that PrP106-126 had a potent chemotactic effect on murine macrophage cell line Ana-1; that multiple signaling pathways might be involved in the PrP106-126-induced macrophage migrations; and that PrP106-126-induced chemotactic activity was similar to that induced by SP. These findings provide new insights into the mechanisms underlying the interaction between PrP and macrophages.

Complete genome sequence of attenuated low-temperature Thiverval strain of classical swine fever virus.

The Thiverval vaccine strain of classical swine fever virus (CSFV) was derived from virulent Alfort strain through the serial passages in cells at 29-30 degrees C. In this study, we determined the complete genome sequence of this strain and found that its genome contains one open reading frame (ORF) that encodes a polyprotein with 3,898 amino acids. The 5'-UTR of Thiverval is 373 nt long with only one mutation at position 220. In contrast, the length of 3'-UTR is highly heterogeneous ranging from 233 to 259 bp. The heterogeneity of length of the 3'-UTR was due to an insertion of a variable length of T-rich sequence ranging from 6 to 32 nt. The insertion may change the structure and free energy of the 3'-UTR, resulting in a destabilization of the 3'-UTR. Sequence alignment of Thiverval and other CSFV strains showed 85.2-99.6% identities at the nucleotide level and 92.5-99.5% at the amino acid level. The phylogenetic tree analysis of the complete ORF, partial region of E2, and NS5B suggests that the CSFV Thiverval strain belongs to genetic group 1 and subgroup 1.1. The results from this study provide insight into the molecular mechanism of the attenuation of Thiverval vaccine strain.

Enhanced susceptibility to chemical induction of ovarian tumors in mice with a germ line p53 mutation.

Mice with a germ line p53 mutation (p53(Ala135Val/wt)) display increased susceptibility to lung, skin, and colon carcinogenesis. Here, we show that p53(Ala135Val/wt) mice developed ovarian tumors significantly more rapidly than their wild-type littermates after 7,12-dimethylbenz(a)anthracene (DMBA) treatment. Approximately 50% of the ovarian tumors in p53(wt/wt) mice and 23% in p53(Ala135Val/wt) mice are adenocarcinomas and the remaining tumors were adenocarcinoma mixed with sarcoma or ovarian sarcomas. All of the p53(Ala135Val/wt) mice had died of ovarian tumors 25 weeks after the initial DMBA treatment, whereas >50% of p53(wt/wt) mice were still alive. These mice not only have a shortened tumor latency but also closely resemble a subset of human ovarian tumors containing the p53 mutation. Microarray and GenMAPP analyses revealed that the mutant p53 (Ala135Val) affected several cellular processes, including the cell cycle, apoptosis, and Wnt pathways. These findings indicate that a germ line p53 mutation significantly enhanced DMBA-induced ovarian tumor development and progression.

Fine mapping and candidate gene analyses of pulmonary adenoma resistance 1, a major genetic determinant of mouse lung adenoma resistance.

Pulmonary adenoma resistance 1 (Par1) is a major genetic determinant of mouse lung adenoma resistance. Although Par1 was previously mapped to mouse chromosome 11 by conventional linkage analyses, its candidate region was broad and undefined. In our present study, we generated Par1 congenic mice using two mouse strains A/J (Par1/-) and Mus spretus (Par1/+). Analyzing these congenic mice enabled us to fine map the Par1 quantitative trait loci (QTL) into a 2.0-cM (2.2 Mb) chromosomal region between genetic marker D11Mit70 and the gene Hoxb9. We then conducted systematic candidate gene screening through nucleotide polymorphism and expression analyses. Genes showing differential lung tissue expression or carrying nonsynonymous single nucleotide polymorphisms were identified and discussed. In particular, we evaluated tumor suppressor gene Tob1 for its Par1 candidacy. Our findings have narrowed the Par1 QTL region and will greatly facilitate the identification of the major genetic determinant of mouse lung adenoma resistance.

p53 Transgenic mice are highly susceptible to 4-nitroquinoline-1-oxide-induced oral cancer.

In this study, we did a bioassay employing mice with a dominant-negative p53 mutation (p53(Val135/WT)) to assess whether a germ-line p53 mutation predisposed mice toward the development of squamous cell carcinomas (SCC) in the oral cavity. Treatment of the mouse oral cavity with 4-nitroquinoline-1-oxide produced a 66%, 91%, and 20% tumor incidence in the oral cavity, esophagus, and forestomach/stomach, respectively, in p53(Val135/WT) mice. In contrast, only a 25%, 58%, and 4% tumor incidence was observed in oral cavity, esophagus, and forestomach/stomach, respectively, in wild-type littermates (p53(WT/WT)). The most striking difference between p53(Val135/WT) and p53(WT/WT) mice following the carcinogen treatment was the higher prevalence and more rapid development of SSC in p53(Val135/WT) mice than in wild-type mice. To identify the precise genes or pathways involved in these differences during tumor development, we examined gene expression profiles of 4-nitroquinoline-1-oxide-treated normal tongues as well as tongue SCC in p53(Val135/WT) and p53(WT/WT) mice. Microarray and GenMAPP analysis revealed that dominant-negative p53 ((135)Valp53) affects several cellular processes involved in SCC development. Affected processes included apoptosis and cell cycle arrest pathways, which were modulated in both tumor and normal epithelium. These results showed that reduction of p53-dependent apoptosis and increases in cell proliferation might contribute to the observed increase in oral cavity and gastroesophageal malignancies in p53(Val135/WT) mice as well as to the more rapid growth and progression of tumors.