DPP3 expression promotes cell proliferation and migration in vitro and tumour growth in vivo, which is associated with poor prognosis of oesophageal carcinoma.

Dipeptidyl peptidase III (DPP3), a zinc­dependent metallopeptidase, is upregulated in a variety of malignancies. However, little is known about its roles in the pathogenesis of these malignancies. The present study was designed to investigate the roles of DPP3 in the pathogenesis and progression of oesophageal cancer (EC). The expression level of DPP3 in EC tissues and adjacent normal tissues was detected in 93 cases of tissue biopsies collected from patients diagnosed with oesophageal carcinoma by immunohistochemistry. The effect of DPP3 expression on cell proliferation, migration or apoptosis was determined in DPP3­depleted EC cells created by infection with lentivirus containing short hairpin RNA specific to the human DPP3 mRNA sequence, followed by detection at the cellular level using a Celigo cell count assay, flow cytometry, wound­healing assay and Transwell assay as well as chip screening with a Human Apoptosis Antibody Array kit, which enables the quantitative detection of 43 apoptosis­related genes. A xenograft model was applied to detect the tumour growth and invasion of DPP3­depleted cancer cells in nude mice. The results revealed that DPP3 expression was elevated in EC tissues compared with adjacent non­tumour tissues, and high DPP3 expression was significantly associated with poor prognosis. DPP3 depletion resulted in reduced cell proliferation and migration and enhanced cell cycle arrest and apoptosis of EC cells and led to the inhibition of tumour growth and invasion in a xenograft model. In addition, DPP3 depletion was associated with the upregulation of the proapoptotic proteins SMAC and p53 and the downregulation of the antiapoptotic proteins clAP­2, IGFBP­2 and TRAILR­4. Finally, DPP3 may promote cell proliferation, migration and survival of EC cells in vitro and tumour growth and invasion of oesophageal carcinoma in vivo, and thus may serve as a molecular target for tumour therapy.

Receptor for activated C kinase 1 promotes cervical cancer lymph node metastasis via the glycolysis­dependent AKT/mTOR signaling.

Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early­stage lymph node metastasis and an extremely poor prognosis. The authors have previously demonstrated that patients with CC have aberrant glycolysis. The upregulation of receptor for activated C kinase 1 (RACK1) is associated with CC lymph node metastasis (LNM). However, its role in mediating aerobic glycolysis in CC LNM remains unclear. In the present study, 1H nuclear magnetic resonance analysis revealed a significant association between RACK1 expression and the glycolysis/gluconeogenesis pathway. Additionally, RACK1 knockdown inhibited aerobic glycolysis and lymphangiogenesis in vitro and suppressed CC LNM in vivo. Furthermore, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was identified as a critical RACK1­regulated pathway that increased lymphangiogenesis in CC. Co­immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin­like growth factor 1 receptor (IGF1R). POU class 2 homeobox 2 (POU2F2) bound to the RACK1 promoter and regulated its transcription, thereby functionally contributing to glycolysis and lymphangiogenesis in CC. Of note, the administration of 2­deoxy­D­glucose, which attenuates glycolysis, inhibited RACK1­induced lymphangiogenesis in CC. The correlations between RACK1, IGF1R, POU2F2 and hexokinase 2 were further confirmed in CC tissues. Thus, RACK1 plays a crucial role in CC tumor LNM by regulating glycolysis via IGF1R/AKT/mTOR signaling. Thus, the targeting of the POU2F2/RACK1/IGF1R/AKT/mTOR signaling pathway may provide a novel treatment strategy for CC.

Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection.

Aberrant metabolic regulation has been observed in human cancers, but the corresponding regulation in human papillomavirus (HPV) infection-associated cervical cancer is not well understood. Here, we explored potential biomarkers for the early prediction of cervical carcinoma based on the metabolic profile of uterine cervical tissue specimens that were positive for HPV16 infection. Fifty-two fresh cervical tissues were collected from women confirmed to have cervical squamous cell carcinoma (SCC; n = 21) or cervical intraepithelial neoplasia (CIN) stages II-III (n = 20). Eleven healthy women constituted the controls (negative controls [NCs]). Real-time polymerase chain reaction (PCR) was performed to detect HPV infection in the tissues. High-resolution magic angle spinning nuclear magnetic resonance was utilized for the analysis of the metabolic profile in the tissues. The expression of rate-limiting enzymes involved in key metabolic pathways was detected by reverse-transcription quantitative PCR. An independent immunohistochemical analysis was performed using 123 cases of paraffin-embedded cervical specimens. A profile of 17 small molecular metabolites that showed differential expression in HPV16-positive cervical SCC or CIN II-III compared with HPV-negative NC group was identified. According to the profile, the levels of α- and ß-glucose decreased, those of lactate and low-density lipoproteins increased, and the expression of multiple amino acids was altered. Significantly increased transcript and protein levels of glycogen synthase kinase 3 beta (GSK3ß) and glutamate decarboxylase 1 (GAD1) and decreased transcript and protein levels of pyruvate kinase muscle isozyme 2 (PKM2) and carnitine palmitoyltransferase 1A (CPT1A) were observed in the patient group (p < 0.05). HPV infection and cervical carcinogenesis drive metabolic modifications that might be associated with the aberrant regulation of enzymes related to metabolic pathways.

CD147 promotes cervical cancer migration and invasion by up-regulating fatty acid synthase expression.

CD147 is a transmembrane glycoprotein that when highly expressed contributes to tumor progression. In the present study, we investigate the clinical relevance of CD147 expression in CCSC tissues and evaluate the association between CD147 expression and cervical lymph node metastasis; CD147 was detected using immunohistochemistry. To functionally analyze the role of CD147 in CCSC cell lines in vitro, SiHa cells were employed, whose endogenous CD147 was artificially downregulated, by using lentiviral-based transfection. Moreover, we have confirmed that knockdown of CD147 led to reduced levels of cellular lipid content in shCD147 cells by BODIPY staining. Cell invasion and migration were analyzed using transwell assays and wound healing. Angiogenesis and lymphangiogenesis were assessed by an endothelial cell tube formation assay. Our data showed that highly expressed CD147 up-regulated the major lipogenic genes, FAS and ACC1 to promote de novo lipogenesis, and knockdown of CD147 significantly inhibited the migration and invasion of CSCC cells. The culture supernatants of CD147 knockdown cells significantly inhibited vascular and lymphatic endothelial cell tube formation. Our results suggest that CD147-mediated FAS and ACC1 overexpression are major regulators of cervical cancer growth and metastasis.

Expression of MMP-9 in different degrees of chronic hepatitis B and its correlation with inflammation.

Expression of matrix metalloproteinase-9 (MMP-9) in different degrees of chronic hepatitis B (CHB) and the correlation of MMP-9 with inflammation was investigated. A total of 96 CHB patients (observation group) admitted and treated in Dongying People's Hospital from December 2016 to November 2017 were selected, and they were compared with 60 healthy individuals (control group) selected in the physical examination center during the same time period. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of MMP-9, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), MMP-9 expression in different inflammation grades and fibrosis stages, and the relationship between MMP-9 and inflammation was analyzed. The levels of MMP-9, TNF-α and IL-6 in serum in the observation group were obviously higher than those in the control group (P<0.05). The rank sum test indicated that there were statistically significant differences in the expression levels of MMP-9 among the inflammation grades G0, G1, G2, G3 and G4 (P<0.05). The expression levels of MMP-9 in fibrosis stages S0, S1, S2, S3 and S4 were detected via the rank sum test, and it suggested that the differences among the 5 stages were statistically significant (P<0.05). Pearsons correlation analysis showed that the MMP-9 expression level was positively correlated with TNF-α and IL-6 (P<0.05). In conclusion, the MMP-9 level is elevated remarkably in patients with varying degrees of CHB, it may play an important role in the pathological progress of liver, and it has a close correlation with inflammation, which can provide a theoretical basis for clinical treatment.