The yin and yang functions of extracellular ATP and adenosine in tumor immunity.

Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immune-activating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.

Down-regulation of HLA-A mRNA in peripheral blood mononuclear cell of colorectal cancer.

PURPOSE: It has been demonstrated that the alteration of human leukocyte antigen (HLA) class I expression frequently occurs in colorectal tumor. Previous studies mainly focused on the expression of HLA-A in tumor cells. The expression of HLA-A in peripheral blood mononuclear cells (PBMC) was unknown. To develop a non-invasive diagnostic method for colorectal cancer (CRC), this work investigated the expression of HLA-A mRNA in PBMC in patients with CRC. METHODS: Real-time quantitative RT-PCR was used to study the expression of HLA-A mRNA in PBMC from 48 patients with colorectal cancer, 38 patients with benign colorectal lesions, 20 patients with rheumatoid arthritis, 20 patients with esophageal cancer and 40 healthy individuals. Protein chip was utilized to detect the levels of serum CEA, CA 19-9, and CA 242 in all the cases. Overall results from the two methods were compared. RESULTS: The relative expression of HLA-A mRNA in PBMC was 1.11 ± 0.45 in healthy group, 0.81 ± 0.42 in benign colorectal lesion group, and 0.39 ± 0.34 in cancer group, respectively. The diagnostic sensitivity of HLA-A mRNA, CEA, CA19-9, and CA242 was 81%, 59%, 61%, and 63%, and their diagnostic specificity was 75%, 64%, 52%, and 67%, respectively. CONCLUSIONS: The expression of HLA-A mRNA in PBMC from colorectal cancer group was significantly lower than those in both benign group and healthy group (P < 0.001). It could be potentially developed as a tumor assistant marker in future.

HLA Class I Expressions on Peripheral Blood Mononuclear Cells in Colorectal Cancer Patients.

OBJECTIVE: To investigate the expression change of human leukocyte antigen (HLA) class I on human peripheral blood mononuclear cells (PBMCs) at both mRNA and protein levels, and to evaluate its roles in the development of colorectal cancer (CRC). METHODS: In the present study, 50 patients with CRC, 35 patients with benign colorectal lesion and 42 healthy volunteers were enrolled. Expression levels of HLA class I mRNA and protein were determined using real-time quantitative reverse transcription PCR (RT-PCR) and flow cytometry analysis, respectively. RESULTS: The expression levels of HLA class I mRNA and proteins were not influenced by age and gender. The relative ratios of HLA class I mRNA were 0.99±0.27 in healthy controls, 0.76±0.19 in benign patients, and 0.48±0.21 in CRC patients. Mean fluorescence intensities of HLA class I were 145.58±38.14 in healthy controls, 102.05±35.98 in benign patients and 87.44±34.01 in CRC patients. HLA class I on PBMCs was significantly down-regulated at both mRNA and protein levels in patients with stage III and IV CRC. CRC patients with lymph node metastasis also showed a decreased HLA class I expression at protein level. CONCLUSION: HLA class I expressions on PBMCs are associated with staging of CRC and lymph node metastasis. Monitoring the expression of HLA class I on PBMCs may provide useful information for diagnosis and metastasis judgement of CRC.

Overexpressed ostepontin-c as a potential biomarker for esophageal squamous cell carcinoma.

BACKGROUND: The metastasis gene osteopontin (OPN) is subject to alternative splicing, which yields three messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive tumors. In the present study, we examined the expression of OPN-c in esophageal squamous cell carcinomas (ESCCs) and assessed its value as a diagnostic biomarker. METHODS: OPN-c expression was assessed by immunohistochemistry in 63 ESCC samples and correlated with clinicopathologic factors. Expression was also examined in peripheral blood mononuclear cells (PBMCs) from 120 ESCC patients and 30 healthy subjects. The role of OPN-c mRNA as a tumor marker was investigated by receiver operating characteristic curve (ROC) analysis. RESULTS: Immunohistochemistry showed that OPN-c was expressed in 30 of 63 cancer lesions (48%)and significantly associated with pathological T stage (P=0.038) and overall stage (P=0.023). Real time PCR showed that OPN-c mRNA was expressed at higher levels in the PBMCs of ESCC patients than in those of healthy subjects (P<0.0001) with a sensitivity as an ESCC biomarker of 86.7%. CONCLUSION: Our findings suggest that expression of OPN-c is significantly elevated in ESCCs and this upregulation could be a potential diagnostic marker.

Inhibition effect of siRNA-downregulated UHRF1 on breast cancer growth.

The UHRF1 gene plays important roles in both cell proliferation through its NIRF_N domains, a PHD domain, an SRA domain, and a RING domain, and multidrug resistance in breast cancer treatment. In this work, a short-hairpin RNA (shRNA) lentiviral system was introduced in two human breast cancer cell lines (MDA-MB-231 and MCF-7) to downregulate the expression of UHRF1 and study the specific inhibition of UHRF1 in breast cancer growth. The effect of UHRF1-shRNA on breast cancer cell proliferation was examined using methylthiazoletetrazolium, bromodeoxyuridine, and colony formation assays. The proliferative potential of the UHRF1-shRNA-treated cells showed a remarkable decrease. Moreover, the downregulation of UHRF1 in both breast cancer cell lines significantly inhibited the colony formation capacity. Results suggested that the inhibition of UHRF1 via an RNA interference lentiviral system may provide an effective way for breast cancer therapy.