The vasoactive intestinal peptide receptor-1(VIPR1) has prominent growth effects on a number of common neoplasms. However, there were contradictions in the effect cross different cancers. We aimed to explore the effect of VIPR1 overexpression on a human lung adenocarcinoma cell line H1299. GEO dataset was used to screen differentially expressed genes in lung adenocarcinoma tissues. The expression of VIPR1 mRNA was determined in the cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to determine VIPR1 protein expression in lung adenocarcinoma and corresponding adjacent tissues (n = 22). Fluorescence real-time quantitative PCR detected the expression of VIPR1 in human normal lung epithelial cell line BEAS-2B and lung adenocarcinoma cell line H1299. Overexpression strategies were employed to assess functions of VIPR1 expression on several malignant phenotypes in H1299. The expression of VIPR1 was lower in lung adenocarcinoma tissues than that in adjacent tissues. Compared with the normal lung epithelial cells BEAS-2B, VIPR1 was down-regulated in lung cancer cells H1299 (P < 0.05). After the overexpression of VIPR1, we found that VIPR1 significantly inhibited growth, migration, and invasion of H1299 cells (P < 0.05). Our findings point out the tumor suppressor roles of VIPR1 in human LUAD pathogenesis.
Although MYC proto-oncogene (C-MYC) amplification has been consistently reported to be a potential marker for prostate cancer (PCa) progression and prognosis, the clinicopathological and prognostic significance of C-MYC protein expression remains controversial. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations is unclear. In the current study, we showed that C-MYC was overexpressed in 16.2% (17/105) of Chinese patients with localized PCa. Overexpression of C-MYC was significantly associated with high Gleason scores (P = 0.012) and high Ki67 labeling index (P = 0.005). C-MYC overexpression was correlated with cancer-related mortality and suggested to be an unfavorable prognostic factor in Chinese PCa patients (P = 0.018). Overexpression of C-MYC is associated with SOX4 overexpression in PCa tissues. Notably, SOX4 is a direct target gene of C-MYC; C-MYC activates SOX4 expression via binding to its promoter. In addition, Co-IP analysis demonstrated a physical interaction between C-MYC and SOX4 protein in PCa cells. Clinically, C-MYC+/SOX4+ characterized poor prognosis in a subset of PCa patients. In total, C-MYC overexpression may contribute to PCa progression by activating SOX4. Our findings highlight an important role of C-MYC/SOX4 in PCa progression in a subset of PCa patients.
Ovarian cancer is one of the most lethal gynecological cancers; owning to its late detection and chemoresistance, understanding the pathogenesis of this malignant tumor is much critical. Previous studies have reported that ubiquitin-specific peptidase 39 (USP39) is generally overexpressed in a variety of cancers, including hepatocellular carcinoma, gastric cancer and so forth. Furthermore, USP39 is proved to be associated with the proliferation of malignant tumors. However, the function and mechanism of USP39 in ovarian cancer have not been elucidated. In the present study, we observed that USP39 was frequently overexpressed in human ovarian cancer and was highly correlated with TNM stage. Suppression of USP39 markedly inhibited the growth and migration of ovarian cancer cell lines HO-8910 and SKOV3 and induced cell cycle G2/M arrest. Moreover, knockdown of USP39 inhibited ovarian tumor growth in a xenograft model. In addition, our findings indicated that cell cycle arrest induced by USP39 knockdown might be involved in p53/p21 signaling pathway. Furthermore, we found that the depletion of USP39 inhibited the migration of ovarian cancer cells via blocking epithelial-mesenchymal transition. Taken together, these results suggest that USP39 may play vital roles in the genesis and progression and may serve as a potential biomarker for diagnosis and therapeutic target of ovarian cancer.
Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.
Early growth response-1 (EGR-1), also termed NEFI-A and Krox-24, as a multi-domain protein is implicated in several vital physiological processes, including development, metabolism, cell growth and proliferation. Previous studies have implied that EGR-1 was producing in response to the tissue injury, immune response and fibrosis. Meanwhile, emerging studies stressed the pronounced correlation of EGR-1 and human cancers. Nevertheless, the intricate mechanisms of cancer-reduce EGR-1 alteration still poorly characterized. In the review, we evaluated the effects of EGR-1 in tumor cell proliferation, apoptosis, migration, invasion and tumor microenvironment, and then, we dwell on the intricate signaling pathways that EGR-1 involved in. The aberrantly expressed of EGR-1 in cancers are expected to provide a new cancer therapy strategy or a new marker for assessing treatment efficacy.
Skin cancer can be classified as cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. Due to the high level of morbidity and mortality, skin cancer has become a global public health issue worldwide while the pathogenesis of skin cancer is still unclear. It is necessary to further identify the pathogenesis of skin cancer and find candidate targets to diagnose and treat skin cancer. A variety of factors are known to be associated with skin cancer including N-glycosylation, which partly explained the malignant behaviors of skin cancer. In this review, we retrieved databases such as PubMed and Web of Science to elucidate its relationship between glycosylation and skin cancer. We summarized some key glycosyltransferases and proteins during the process of N-glycosylation related to skin cancer, which was helpful to unmask the additional mechanism of skin cancer and find some novel targets of skin cancer.
Prostate cancer (PCa) is one of the most common malignancies in men worldwide. This study was designed to investigate the potential of Ribosomal Protein L22-like1 (RPL22L1) and Ribosomal Protein S21 (RPS21) as diagnostic and prognostic biomarkers for PCa. First, RPL22L1 and RPS21 were screened as the key molecular of PCa by bioinformatics analysis. Subsequently, the prostate tissue samples were stained for antibodies against RPL22L1 and RPS21. The unbiased signal quantification was performed by ImageJ software, and the results showed that the expression of RPL22L1 and RPS21 exhibited significant differences between the PCa tissues and the normal prostate tissues. Receiver-operating characteristics (ROC) curves were prepared, and then the area under the curve (AUC) values of RPL22L1 and RPS21 were calculated as 0.798 and 0.768, and the likelihood ratio (LR) values of RPL22L1 and RPS21 were calculated as 2.86 and 2.53. These data implied that the over-expression of RPL22L1 and RPS21 is associated with the presence of PCa. The further analysis suggested that the expression of RPL22L1 and RPS21 were significantly higher in high Gleason grade than they were in low Gleason grade. In addition, in vitro studies were undertaken to evaluate the roles of RPL22L1 and RPS21 in PCa. The results revealed that these genes promote PCa cell proliferation, migration and invasion, and inhibit PCa cell apoptosis. Taken together, these data showed that RPL22L1 and RPS21 exhibited higher expression in human prostate cancer tissue, and involved in PCa cell proliferation and invasion. This research provided a novel insight into diagnostic and prognostic biomarkers for PCa.
Testicular germ cell tumors are the most frequent malignancies found in men between 15 and 44years old. Although cellular apoptosis susceptibility (CAS) was demonstrated to be upregulated in breast cancer and colon cancer, the expression of CAS in the human testis and testicular germ cell tumors remained elusive. In the present study, CAS-positive signals were detected in the normal testicular tissues, cancer adjacent normal testicular tissues, seminoma, yolk sac tumor, and teratoma. Interestingly, the expression level of CAS in testicular germ cell tumors (TGCTs) (but not seminoma) was significantly lower than that of human testicular tissues and cancer adjacent normal testicular tissues, suggesting that decreased CAS contributed to the progression of TGCTs. Notably, the expression of CAS in seminoma was significantly higher than that of in the non-seminomas, consistent with the results from TCGA database. Furthermore, the localization of CAS is mainly restricted in the nucleus in the lesions of normal human testicular tissue and cancer adjacent normal testicular tissue. Although the expression of CAS was not significantly different between normal testicular tissue and seminoma, CAS was more enriched in cytoplasm in seminoma compared to the normal, cancer adjacent tissue and other types of TGCTs. The current results demonstrated reduced expression of CAS in the human testicular germ cell tumors and the CAS translocation from the nuclear to cytoplasm in seminoma, thereby supporting a possible role in normal testis function and in the development of seminoma.
The development of drug resistance affecting the prognosis of patients with hepatocellular carcinoma (HCC) leads to low survival rate of HCC patients. Caffeine is reported to have a function of protecting the liver and anti-tumor activity. Therefore, caffeine may be an ideal enhancer for HCC chemotherapy regimens. Our study showed that the combination of caffeine and 5-FU significantly inhibited the proliferation of HCC cells in vivo and in vitro comparing with caffeine or 5-FU monotherapy. The CI values of caffeine (0.5 mM) combined with 5-FU (25, 50 mu M) were all less than 1, confirming that the utilization of drug combination has a synergistic inhibitory effect on the proliferation of HCC cells. Meanwhile, results of Western blot and TUNEL assays demonstrated that the apoptotic level of HCC cells in the combined group was significantly increased. The protein expression level of cleaved PARP was up-regulated, while the protein level of Bcl-2 and Bcl-xL was down-regulated. In addition, we found that ROS levels were increased in the 1 mM caffeine and 25 mu M 5-FU combination group comparing with the control or single drug group. Taken together, this is the first study to demonstrate that the combination of caffeine and 5-FU inhibits HCC cells proliferation and promotes cellular apoptosis by regulating intracellular ROS production. The present data provides a basis for the application of caffeine combined with 5-FU as a novel chemotherapy regimen for HCC.
Small cell carcinoma of the bladder (SCCB) is a rare disease associated with high invasiveness and mortality. Histologically, SCCB is difficult to distinguish from small cell lung cancer (SCLC); however, it shares more similar molecular alterations with urothelial carcinoma (UC). As a result, now, the widely accepted theory about the cells of origin is that SCCB and UC probably have a common clone origin. Even the former probably comes from a preexisting UC. At present, given its rarity, early diagnoses, treatments, and follow-ups are not well established, which are vital to patients with SCCB. Inspirationally, in recent years, with the development of molecular diagnostic methods, molecular alterations of SCCB have been understood partially, which are propitious to excavate new potential therapeutic strategies and establish sound follow-ups. Therefore, the future will be light for patients with SCCB.
Oncolytic adenovirus is an emerging alternative to current therapeutics. The adenoviral E1A, the first protein expressed upon oncolytic adenoviral infection, has been identified as an antitumor agent, but the mechanisms of its tumor inhibition ability are unclear enough. Decorin is ubiquitous in the extracellular matrix (ECM), which regulates multiple functions through interaction with ECM. Here, we intended to explore the effects of adenoviral E1A on the tumor extracellular matrix during gene therapy. We demonstrated that reduced decorin expression was found in patients with lung cancer. The adenoviral E1A or a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa, 120-127aa deletion) could increase the expression of decorin and down-regulate VEGF, two members of tumor ECM, involved in both vasculogenesis and angiogenesis. E1A/mE1A-mediated suppressing the migration and invasion ability of tumor cells was depended on decorin. E1A interacted with decorin directly and induced the proteasomal degradation of VEGF. In addition, E1A or mE1A can inhibit tumor growth in a subcutaneous lung cancer xenograft model. It suggested that decorin might be a crucial mediator among ECM components for adenoviral E1A-mediated antitumor activities. These studies on adenovirus E1A provide a new mechanism for the emerging therapies of tumor gene therapy.
Our previous work has demonstrated that paclitaxel can induce the formation of polyploid giant cancer cells (PGCCs) and inhibit tumor growth by reprogramming ovarian cancer epithelial cells to a benign fibroblastic state via epithelial-mesenchymal transition. Here, triptolide (TPL) was used to treat the breast and ovarian cancer lines. The morphologic characteristics and EMT-related protein expression were studied in different generation of cancer cells after TPL treatment. When BT-549 and HEY cells reached 80-90% confluence, TPL was added to BT-549 for 48 h and HEY for 9 h at a concentration of 40 ng/ml. Scattered PGCCs survived from TPL treatment and generated daughter cells, and then were cultured in medium without TPL for at least ten generation. Western blot analysis and immunocytochemical staining were performed to detect the expression levels and subcellular location of EMT-related proteins in control cells and different generation of TPL-induced PGCCs with daughter cells. Furthermore, wound-healing, transwell, cell counting kit-8, and MTT assay were used to compare the alternation of migration, invasion, and proliferation among control cells and different generation of TPL-induced PGCCs with daughter cells. Scattered PGCCs survived from the treatment of TPL and produced small-sized daughter cells 20-30 days after treatment. Compared to the control cells, the first generation of TPL-induced PGCCs with their daughter cells differentially expressed EMT-related proteins including fibronectin, E-cadherin, vimentin, and Twist, and had lower migration, invasion, and proliferation abilities. The abilities of migration, invasion, and proliferation of TPL-induced PGCCs with their daughter cells gradually enhanced as the passages increasing, and markedly exceeded the control cells in the tenth generation. TPL-induced PGCCs with their daughter cells gradually obtain the abilities of invasion and metastasis in vitro as the number of passage increasing, which can be used to mimick the cancer cells subjected to anti-cancer drugs in vivo and may provide some new insights to explore the mechanism of cancer invasion, metastasis and relapse after chemotherapy.