The epidemiology and clinical outcome of gastrointestinal mucinous adenocarcinoma (MA) are not well illustrated. The present study aimed to explore the evolving epidemiology and prognostic factors that affect the survival of patients with MA in the gastrointestinal tract. A retrospective and population-based study was conducted to determine the annual age-adjusted incidence, overall survival (OS) and survival trend of gastrointestinal mucinous MA using nationally representative data from the Surveillance, Epidemiology, and End Results (SEER) program between 2000 and 2014. A Kaplan-Meier curve and a Cox proportional regression model were used to evaluate prognostic factors for this disease. Of the 51632 cases, females accounted for 50.5% (26058). The annual incidence of MA steadily decreased from 2000 to 2014. This trend occurred across all stages, grades and sites, apart from the appendix. In the SEER 18 registry grouping (2000-2014), the highest incidence was 3.333 per 100,000 persons for the colon. The median OS varied significantly between different primary sites, stages, grades, and age of clinical diagnosis, and the time period of diagnosis, according to a multivariable analysis. The five-year OS of gastrointestinal MA improved gradually between 2000 and 2014. The improvement in survival over the same interval was more pronounced in the subgroup of distant gastrointestinal MA. All sites along the alimentary tract, with the exception of the appendix, showed a decrease in the incidence of MA. Improved survival rates were observed for most of the gastrointestinal tract, especially for patients with advanced stage disease. MA in the upper gastrointestinal tract was less frequent but had poorer survival than colorectal MA. Clinicians should consider the primary tumour site when making therapeutic guidelines and treatment decisions for gastrointestinal MA.

The aim of the present study was to use a competing risk model to analyze the prognostic value of mucinous adenocarcinoma (MAC) in patients with colorectal cancer (CRC). An additional aim was to construct nomograms for estimating the 3- and 5-year overall survival (OS) and cancer specific survival (CSS) rates of patients with primary CRC with MAC. The data were extracted from the Surveillance, Epidemiology, and End Results database, and a Multivariate Cox model and competing risk model were applied to assess the OS and CSS. Cox-based and competing risk-based nomograms were constructed and internally validated by discrimination and calibration, using the bootstrapping method with 1,000 times replicates. A total of 13,035 MAC and 61,958 non-mucinous adenocarcinoma (NMAC) CRC patients were enrolled in the present study. Compared with NMAC, MAC patients had a poorer OS and CSS time in the overall population, and in subgroups that comprised metastatic, non-metastatic, male, site of sigmoid colon, rectosigmoid junction and rectal CRC cases (HR>1; P<0.05). The Cox and competing risk-based nomograms showed effective discrimination and calibration. In conclusion, MAC was associated with poor OS and CSS in patients with CRC of the distal colon and rectum. The nomograms of primary CRC patients with MAC may aid the identification of individual patients with a high risk of overall mortality and cancer-associated mortality within 3 or 5 years.

Adenocarcinoma is the most common histological type of lung cancer and has various histologic subtypes, including lepidic, papillary, acinar and invasive mucinous adenocarcinoma. Histologic subtypes are associated with tumor invasiveness. For example, the lepidic subtype is less invasive than the papillary/acinar subtype. Trefoil factor 3 (TFF3) is a small secreting protein that is a member of the trefoil factor family, which is involved in mucosal stabilization and repair through its mitogenic and antiapoptotic activities. TFF3 overexpression is associated with various types of cancer. In lung cancer, TFF3 is expressed significantly in adenocarcinoma. However, the relationship between TFF3 expression and histologic subtypes in lung adenocarcinoma is unclear. The current study immunohistochemically revealed that, beside invasive mucinous carcinoma, the expression of TFF3 in papillary and acinar adenocarcinoma was significantly higher than that in lepidic adenocarcinoma. To further confirm these results, the expression of TFF3 in cases with both lepidic and papillary/acinar areas were examined. The expression of TFF3 in papillary/acinar areas was significantly higher when compared with lepidic areas in a single sample. Furthermore, using the lung adenocarcinoma cell line A549, TFF3-knockdown cells were generated. The results revealed that knockdown of TFF3 attenuated invasion. In vitro and immunohistochemical assays using clinical samples demonstrated that TFF3 expression was associated with lung adenocarcinoma invasiveness. To the best of our knowledge, the current study is the first to report that TFF3 expression was associated with the histologic subtypes of lung adenocarcinoma.

Na+/H+ exchanger isoform 1 (NHE1), which is a regulator of intracellular and extracellular pH via ion exchange, has been demonstrated to serve an important role in cell differentiation, migration and invasion in solid tumors and hematological malignancies. However, the potential role of NHE1 in epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression pattern and the prognostic value of NHE1 were investigated in EOC. EOC tissues, non-cancerous tumors and normal ovarian tissues were collected, and the expression levels of NHE1 were determined using the reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The expression pattern of NHE1 was also evaluated in ovarian cancer cell lines using western blotting and immunofluorescence. In addition, the association between the NHE1 expression pattern and the clinicopathological features and the clinical prognosis of patients with EOC was also analyzed. The expression levels of NHE1 were identified to be significantly increased in EOC tissues compared with non-cancerous tumors and normal ovarian tissues (P<0.05). Furthermore, the increased expression of NHE1 was associated with an advanced International Federation of Gynecology and Obstetrics stage (FIGO III-IV; P<0.001) and the presence of high-grade carcinoma (grades 2-3, P<0.001). Overexpressed NHE1 was identified as a risk factor of shorter PFS (P<0.001) and OS (P<0.001). A multivariate Cox's regression analysis revealed that NHE1 was an independent prognostic factor for the prediction of the outcome of patients with EOC. NHE1 may, therefore, serve as a potential therapeutic target to inhibit tumor aggressiveness.

The tumor necrosis factor α-induced protein 8 (TNFAIP8)-like (TIPE) protein family comprises four members, namely TNFAIP8, TIPE1, TIPE2 and TIPE3, which are involved in multiple processes in cancer. The current study aimed to investigate the expression patterns and potential clinical roles of the TIPE family members in human colorectal cancer (CRC). Paired tumor and adjacent tissue samples were collected from 49 patients with CRC, and the relative mRNA expression levels of the TIPE family members in these samples were evaluated by using reverse transcription-quantitative PCR, and the protein levels in five randomly selected pairs of tumor and adjacent tissue samples were detected by western blot analysis. The mRNA expression levels of the TIPE family members were significantly downregulated in CRC tumor tissues compared with those in the adjacent tissues; however, within each sample, TNFAIP8 and TIPE3 protein levels were only partially consistent with their mRNA levels. In addition, the mRNA expression levels between each pair of TIPE family members exhibited a positive linear relationship, and TIPE2 mRNA levels exhibited strong linear associations with those of TNFAIP8 and TIPE1. TNFAIP8 mRNA expression levels in tumor tissues were significantly associated with the tumor differentiation grade, and TIPE2 mRNA expression levels in tumor tissues were significantly associated with sex. TIPE1 and TIPE3 mRNA expression levels in tumor tissues exhibited no associations with patient clinicopathological characteristics. In addition, the mRNA expression patterns of the TIPE family members were analyzed using data from The Cancer Genome Atlas data set, and the results also demonstrated that TNFAIP8, TIPE2 and TIPE3 mRNA levels were downregulated in patients with colon adenocarcinoma compared with those in normal controls. These results provided evidence that the four members of the TIPE family may affect each other to mediate the carcinogenesis of CRC, and that TIPE2 may serve an important role in CRC.

Cancer metastasis, particularly multiple metastatic cancer, is a significant event that affects patient prognosis. However, single metastasis can be treated by partial resection, although the clinicopathological and molecular profile of single lung metastasis has not been thoroughly elucidated. The present study examined tumor heterogeneity by comparing the mutation status between primary colorectal cancer (CRC) and corresponding metastatic lesions to identify prognostic factors associated with single lung metastasis and multiple metastases. The present study enrolled 31 cases of CRC; 20 cases with multiple metastases and 11 cases with single lung metastasis. Clinicopathologically, all cases with multiple metastases were tubular adenocarcinoma, and 3/11 cases with single metastasis were mucinous adenocarcinoma originating from the left side, the remaining 8 cases were tubular adenocarcinoma from the left side. CRC cases with multiple metastases exhibited more frequent vascular invasion, but not lymphatic invasion, than those with single lung metastasis. Furthermore, CRC with multiple metastases was associated with strong tumor budding (P=0.04). Patients with CRC with multiple metastases had lower recurrence-free survival rates compared with those with single lung metastasis (P=0.02). However, there was no significant difference between these two groups in terms of overall survival rates. A next-generation sequencing cancer hotspot panel was used to analyze a heterochronous multiple metastases case, including brain metastasis. Sanger sequencing, immunohistochemistry and microsatellite instability were examined for all 31 cases to reveal the molecular features. KRAS and TP53 mutation signatures were largely preserved throughout the metastatic events. TP53/APC mutations and overexpression of p53 appeared to be associated with the presence of lymphovascular invasion and strong tumor budding, respectively, although these differences were not statistically significant. Early relapses in patients with CRC could be a sign for eventual multiple metastases, although these may not affect the overall survival of patients with CRC. Considerable mutational changes were seemingly rare during metastatic events in patients with CRC.

Thymidine phosphorylase (TP) is structurally similar to platelet-derived endothelial cell growth factor, and it activates 5-fluorouracil (5-FU) prodrugs and also promotes angiogenesis. In the present study, the possibility of using TP expression as a biomarker for 5-FU prodrugs, and the significance of TP as an angiogenic factor, were investigated in patients with gynecological tumors. The subjects enrolled in the study were 188 patients with gynecological tumors who provided informed consent and underwent tumor resection at the Department of Obstetrics and Gynecology of Tokai University Hospital between February 2002 and January 2010. Measurement of the enzymatic activity of TP and dihydropyrimidine dehydrogenase (DPD) was performed by enzyme-linked immunosorbent assay. In addition, immunohistochemistry (IHC) analysis of microvessels by monochrome imaging, western blotting and reverse transcription-polymerase chain reaction were performed. The mean TP activity and the TP/DPD ratio were increased in squamous cell carcinoma of the cervix (306.9 and 2.2 U/mg protein, respectively) and adenosquamous carcinoma (317.6 and 1.4 U/mg protein, respectively) compared with benign tumors and other malignancies, including endometrial (uterine) carcinoma, ovarian serous adenocarcinoma and ovarian mucinous adenocarcinoma. However, these parameters were also elevated in other histological types of cancer such as clear cell adenocarcinoma of the ovary (115.2 and 2.1 U/mg protein, respectively), in which the microvessel area was the largest of all the histological types analyzed. Since high TP expression and a high TP/DPD ratio were identified in other tumors besides cervical cancer, it is possible that patients for whom 5-FU prodrugs are indicated could be selected appropriately if their TP activity is determined and their TP expression is analyzed by IHC prior to initiation of the treatment.

MicroRNAs serve important roles in various diseases, particularly cancer. microRNA-106a (miR-106a) exhibits abnormal expression and oncogenic activity in carcinogenesis. The clinical significance of the abnormal expression of miR-106a in colorectal cancer is poorly understood. In the present study, miR-106a expression from colorectal cancer tissues was quantified using the reverse transcription-quantitative polymerase chain reaction. The overexpression or knockdown of miR-106a was performed by transfection with microRNA mimic or inhibitor in human colorectal carcinoma HCT116 cells. The overexpression of miR-106a promoted viability and inhibited apoptosis in colorectal cancer cells. The association between miR-106a expression and clinicopathological factors was analyzed, and it was identified that miR-106a exhibited significantly increased expression in adenocarcinoma tissues compared with in mucinous carcinoma tissues, and the expression of miR-106a was identified to be associated with the depth of invasion and differentiation. The expression of miR-106a in plasma was also determined and it was identified that increased expression of miR-106a, as a characteristic of patients with colorectal cancer, may be distinguished from that of other patients by digitization of the areas under the receiver operating characteristic curves. These data suggested that miR-106a is a potential biomarker in the diagnosis of colorectal carcinoma. However, the underlying molecular mechanism of miR-106a-promoted viability and inhibition of apoptosis requires further investigation.

Ovarian cancer affects >295,000 women worldwide and is the most lethal of gynaecological malignancies. Often diagnosed at a late stage, current research efforts seek to further the molecular understanding of its aetiopathogenesis and the development of novel biomarkers. The present study investigated the expression levels of the glucogenic hormone asprosin [encoded by fibrillin-1 (FBN1)], and its cognate receptor, olfactory receptor 4M1 (OR4M1), in ovarian cancer. A blend of in silico open access The Cancer Genome Atlas data, as well as in vitro reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry and immunofluorescence data were used. RT-qPCR revealed expression levels of OR4M1 and FBN1 in clinical samples and in ovarian cancer cell lines (SKOV-3, PEO1, PEO4 and MDAH-2774), as well as the normal human ovarian surface epithelial cell line (HOSEpiC). Immunohistochemical staining of a tissue microarray was used to identify the expression levels of OR4M1 and asprosin in ovarian cancer samples of varying histological subtype and grade, including clear cell carcinoma, serous ovarian cancer and mucinous adenocarcinoma. Immunofluorescence analysis revealed asprosin expression in SKOV-3 and HOSEpiC cells. These results demonstrated the expression of both asprosin and OR4M1 in normal and malignant human ovarian tissues. This research invokes further investigation to advance the understanding of the role of asprosin and OR4M1 within the ovarian tumour microenvironment.

CD24, which is upregulated in several human malignancies, is related to Epithelial-mesenchymal-transition (EMT) and has characteristics of cancer stem-like cells, especially in cisplatin-resistant ovarian carcinoma cells. Drug delivery systems represent a promising therapeutic approach for diseases with treatment resistance, and the present study investigated a novel CD24-targeted drug delivery system for advanced ovarian carcinoma. We produced liposomal cisplatin with a red fluorescent substance - cyanine 5.5 (GL-CDDP-Cy5.5). In order to target CD24-positive cells, an anti-CD24 monoclonal antibody was modified to the above drug (CD24-GL-CDDP-Cy5.5). Specific uptake of CD24-GL-CDDP-Cy5.5 was confirmed using a therapeutically resistant ovarian cancer cell line, Caov-3 cells. Antitumor effects of CD24-GL-CDDP-Cy5.5 were then evaluated in Caov-3 ×enograft mice. CD24-GL-CDDP-Cy5.5 showed more specific uptake by flow cytometry than GL-CDDP-Cy5.5. In xenograft mice, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 treatment had significantly higher platinum concentration in disseminated tumor cells than cisplatin (P<0.05). Moreover, CD24-GL-CDDP-Cy5.5 suppressed tumor growth and prolonged survival time compared with other treatments. Median survival times of the control, cisplatin, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 groups were 37, 36, 46 and 54 days after inoculation, respectively. Immunohistochemical analysis showed that CD24-GL-CDDP-Cy5.5 treatment, compared with GL-CDDP-Cy5.5, decreased the number of CD24-positive cells and suppressed the EMT phenomenon significantly (P<0.05). The present study demonstrated that CD24-GL-CDDP-Cy5.5, compared with other treatments, improved therapeutic efficacy. The present results suggested the potential for targeting anticancer therapeutics for CD24-positive cells to prevent disease progression.