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MicroRNA (miR)-1246 is abnormally expressed and has pro-oncogenic functions in multiple types of cancer. In the present study, its functions in breast cancer and the underlying mechanisms were further elucidated. The clinical relevance of miR-1246 was analyzed and its expression in clinical specimens and cell lines was examined by reverse transcription-quantitat000000ive PCR analysis. FACS was used to detect cell apoptosis and mitochondrial transmembrane potential. A Transwell system was used to detect cell migration and invasion. Luciferase assay was used to confirm the target gene of miR-1246. Xenograft and metastasis mouse models were constructed to determine the function of miR-1246 in vivo. miR-1246 was found to be negatively associated with overall survival in breast cancer. miR-1246 inhibitor could effectively increase the cytotoxicity of docetaxel (Doc) by inducing apoptosis, and impair cell migration and invasion by suppressing epithelial-to-mesenchymal transition. Nuclear factor (erythroid 2)-like factor 3 (NFE2L3) was confirmed as a new target gene of miR-1246, and its overexpression was shown to reduce drug resistance and migration of MDA-MB-231 cells. More importantly, NFE2L3-silencing attenuated the effect of miR-1246 inhibitor. Finally, the inhibition of miR-1246 effectively enhanced the cytotoxicity of Doc in xenografts and impaired breast cancer metastasis. Therefore, miR-1246 may promote drug resistance and metastasis in breast cancer by targeting NFE2L3.

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An increased peripheral soluble HLA-G (sHLA-G) expression has been observed in various malignancies while its prognostic significance was rather limited. In this study, the prognostic value of plasma sHLA-G in 178 colorectal cancer (CRC) patients was investigated. sHLA-G levels were analyzed by specific enzyme-linked immunosorbent assay. Data showed sHLA-G levels were significantly increased in CRC patients compared with normal controls (36.8 U/ml vs 25.4 U/ml, p = 0.009). sHLA-G in the died were obviously higher than that of alive CRC patients (46.8 U/ml vs 27.4 U/ml, p = 0.012). Patients with sHLA-G above median levels (≥ 36.8 U/ml, sHLA-Ghigh) had a significantly shorter survival time than those with sHLA-Glow (< 36.8 U/ml, p < 0.001), and sHLA-G could be an independent prognostic factor for CRC patients. With stratification of clinical parameters in survival by sHLA-Glow and sHLA-Ghigh, sHLA-G exhibited a significant predictive value for CRC patients of the female (p = 0.036), the elder (p = 0.009), advanced tumor burden (T3 + 4, p = 0.038), regional lymph node status (N0, p = 0.041), both metastasis status (M0, p = 0.014) and (M1, p=0.018), and clinical stage (I + II, p = 0.018), respectively. Summary, our data demonstrated for the first time that sHLA-G levels is an independent prognosis factor and improves the prognostic stratification offered by traditional prognosticators in CRC patients.

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Human leukocyte antigen-G (HLA-G) is a novel tumor marker. Increased level of soluble HLA-G (sHLA-G) in various tumor types has been reported. However, the potential diagnostic value of sHLA-G with other tumor markers in gastric cancer (GC) diagnosis is yet to be explored. In this study, plasma level of sHLA-G was measured in 81 GC patients, 53 benign gastric disease patients and 77 normal controls by ELISA. The serum levels of alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cancer antigen 19-9 (CA19-9) and cancer antigen 72-4 (CA72-4) were also determined. Data showed that plasma level of sHLA-G in GC was dramatically increased compared with normal controls and benign gastric disease patients (both p<0.001). The AUC for sHLA-G was 0.730 (p<0.001), superior to serum AFP, CEA, CA125, CA19-9 and CA72-4. After evaluating three cut-offs of sHLA-G, we concluded sHLA-G (cut-off at 128U/ml) plus CA125 in two-biomarker panel test and CA125 plus CA199 plus sHLA-G or CA125 plus CA724 plus sHLA-G in three-biomarker panel test were better choices for GC discrimination. Our findings indicated that sHLA-G was a potential biomarker for GC diagnosis and the combination of sHLA-G with CA125, CA19-9 and CA72-4 can improve the clinical screening and diagnosis for GC.

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HLA-G is an immune tolerant with seven isoforms. HLA-G expression was observed to be associated with tumor cell immune escaping, invasion and metastasis, and with poor prognosis in cancer patients. Different types of HLA-G isoforms could be expressed in clinical settings when meet different cellular and environmental conditions. Lesion total HLA-G expression detected by the monoclonal antibody (mAb) 4H84 was widely investigated in previous studies, while specific HLA-G isoforms such as HLA-G5/-G6 remains to be clarified. In this study, 118 primary ovarian cancer lesions were probed with mAb 5A6G7 which recognizes HLA-G5/-G6 was performed by immunohistochemistry. Data showed that HLA-G5/-G6 was expressed in 79.7% (94/118) of these ovarian cancer lesions, where HLA-G5/-G6 expression was observed in 75.7% (53/70) serous, 63.6% (7/11) mucinous cystadenocarcinoma and in 100% (11/11) endometrioid adenocarcinoma, in 85.7% (6/7) clear cell carcinoma, 100% (10/10) sex cord-stromal tumor and 77.8% (7/9) germ cell tumors. However, lesion HLA-G5/-G6 expression was unrelated to histological type, patient age, FIGO stage and patient survival. Unlike total HLA-G expression, no clinical significance of HLA-G5/-G6 expression in ovarian cancer lesion was observed in this study. Our findings indicated that different HLA-G isoforms might have different biological functions in malignancies.

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The immunotolerant HLA-G could generate seven isoforms including HLA-G1--G7. The suppressive function of either HLA-G1 or HLA-G5 isoform to NK cell cytolysis has been well established. Whether HLA-G1 and HLA-G5 isoform have an additive effect on the cytolysis of NK cells remain to be explored. In this study, effects of expression of HLA-G1 and HLA-G5 isoforms and their combination on NK cytolysis was investigated. NK cell cytolysis was analyzed by detecting the NK cell surface CD107a expression. In this study, data showed that the inhibition capacity is dependent on the level of both HLA-G1 and HLA-G5 expression, but the HLA-G5 isoform has a more potent inhibition effect on the NK cytolysis (p<0.01). Furthermore, HLA-G1 and HLA-G5 have an additive effect on the suppression of NK cell cytolysis. Our study provided further understanding for the roles of HLA-G1 and HLA-G5 isoform expression in target cells immune escaping from NK cells.

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The immunotolerant human leukocyte antigen (HLA)-G has direct inhibitory effects on natural killer cells, dendritic cells, T cells and can indirectly induce tolerant regulatory cells. The significance of the aberrant HLA-G expression in malignant contexts has been intensively investigated. In the current study, HLA-G expression in 22 normal cervical tissues, 14 cervical intraepithelial neoplasia (CIN) patients and 129 patients with squamous cell cervical cancer were examined using immunohistochemistry. The association of HLA-G expression with disease progression was calculated with the Pearson Chi-square test. It was found that HLA-G expression was absent in normal cervical tissues, and that HLA-G expression was increased from patients with CIN III (35.7%, 4/14) to patients with cervical cancer (62.8%, 81/129). Among the cervical cancer patients, HLA-G expression in FIGO stage I, II, and stage III+IV was 53.6% (45/84), 76.3% (29/38), and 100.0% (7/7), respectively. Taken together, our findings indicated that HLA-G expression was associated with the disease progression in patients with cervical cancer.

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Aberrant HLA-G expression is associated with tumor invasiveness and poor clinical prognosis; however, there is a lack of preclinical animal model to address whether HLA-G plays a causal role in the unfavorable prognosis of malignancies. In the current study, ovarian carcinoma cell lines (HO-8910 and Ovcar-3) were transfected with HLA-G gene. HLA-G expression was analyzed with western blot and flow cytometry. Transwell experiment was performed to analyze the cell migration and invasion capability and/or multicellular spheroid formation was investigated with the 3D culture assay in vitro. The effects of HLA-G expression for tumor cell organ metastasis and for mouse survival was analyzed with the Balb/c nu/nu mouse model. Our data showed that HO-8910-G and Ovcar-3-G cells are of higher invasion potential compared with the parental HO-8910 and Ovcar-3 cells. Multicellular spheroid formation exists only in HO-8910-G cells in a 3D culture assay. In Balb/c nu/nu mouse model, widespread metastasis was observed in mice xenografted with HO-8910-G cells, but not in the group with parental cells. Mouse survival was dramatically decreased in HO-8910-G and Ovcar-3-G xenografted mice than that with HO-8910 and Ovcar-3 cells, respectively. In summary, our study provided the first evidence that HLA-G expression is associated with tumor metastasis and with poor survival in an animal model with ovarian cancer.

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Human leukocyte antigens (HLA)-E, -F and -G are referred to as non-classical HLA class I antigens. Among them, the clinical relevance of HLA-E and HLA-G has been intensively investigated, but that of HLA-F remains unknown. In this study, HLA-F expression in 83 primary non-small-cell lung cancer (NSCLC) lesions and corresponding adjacent normal tissues were analyzed with immunohistochemistry. Relevance of HLA-F expression with clinical parameters and patient survival was evaluated. Data revealed that HLA-F expression was observed in 24.1% (20/83) of the NSCLC primary lesions but not in adjacent normal lung tissues. HLA-F expression was not significantly relative to clinicoparameters including patient age, gender, tumor histological type, grade of tumor differentiation and TNM stage. Unexpectedly, patients with HLA-F positive expression had a significantly worse prognosis (p=0.017). The median overall survival for the patients with HLA-F positive was 10.0 months (range: 4.4-18.3 months) and with HLA-F negative was 17.0 months (range: 10.4-23.6 months), respectively. Multivariate analysis revealed that HLA-F could be an independent prognostic factor with the hazard ratio of 5.12 [95% confidential Intervals (CI): 1.8-14.3]. Summary, this study was for the first time to provide the evidence that HLA-F expression was of clinical significance in tumor patients and that its expression was associated with a poor survival and could be a prognostic indicator in patients with NSCLC.

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Human leukocyte antigen (HLA)-G inhibits functions of immune component cells and promotes malignant cells evading from antitumor immunity. We investigated the clinical relevance of HLA-G expression in esophageal squamous cell carcinoma (ESCC). In our study, HLA-G expression in 79 primary ESCC lesions and corresponding adjacent normal tissues were analyzed with immunohistochemistry. Soluble HLA-G (sHLA-G) in plasma was detected with enzyme-linked immunosorbent assay (ELISA) in 41 ESCC patients (including 19 case-matched lesions and plasma samples) and in 153 normal healthy controls. HLA-G expression was observed in 65.8% (52/79) of the ESCC lesions but not in adjacent normal esophageal tissues. HLA-G expression was more frequently observed in patients with advanced disease stage (III/IV vs. I/II, p = 0.01). Patients with HLA-G expression had a significantly worse survival, and HLA-G could be an independent prognostic factor. sHLA-G levels in plasma were significantly increased in patients compared to normal controls (median: 152.4 U/ml vs. 8.9 U/ml, p < 0.001). The area under receiver-operating characteristic (ROC) curve for sHLA-G in plasma was 0.992. However, no significant correlation was found between sHLA-G in plasma and clinical parameters studied. In conclusion, our findings indicated that HLA-G expression in ESCC is associated with poor survival and could be a prognostic indicator. Furthermore, increased levels of sHLA-G in plasma might be a useful preoperative biomarker for diagnosis.

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