High expression of lncRNA HSD11B1-AS1 indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non-coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11β-hydroxysteroid dehydrogenase type 1-antisense RNA 1 (HSD11B1-AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1-AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1-, 3- and 5-year overall survival, progression-free interval and disease-specific survival. In vitro experiments verified the decreased HSD11B1-AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit-8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1-AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN-γ and -α response, TNF-α signaling via NF-κB and IL-2/STAT-5 and IL-6/JAK/STAT-3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1-AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1-AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.     

Relationship between human papillomavirus infection and overexpression of p53 protein in cervical carcinomas and lymph node metastases

Overexpression of p53 protein is common in cervical carcinoma. We investigated archival biopsies from 26 cervical cancer patients (24 with available lymph nodes) to determine the relationship between p53 overexpression and HPV infection at the cervix and lymph nodes. Twelve cervical carcinoma patients had p53 protein in cervical biopsies detectable by immunohistochemistry using monoclonal antibody DO-1, and 22 were positive for HPV DNA in polymerase chain reaction assays (16 contained HPV-16; 3, HPV-18; and, 3 HPV-X). Seven cervical cancer patients had one or more lymph nodes positive for p53 protein, and all but one of these were concordantly p53 positive at the cervix. However, detection of p53 protein in cervical biopsies was predictive neither of the expression of p53 at draining lymph nodes (P > 0.1) nor of the occurrence of metastases (P > 0.1). Fourteen patients were positive at one or more lymph nodes for HPV DNA. Cervical positivity for HPV DNA was associated significantly with concordant HPV positivity at the lymph nodes (P = 0.039) and was predictive of metastases (P = 0.019). There was no association between positivity for p53 and for HPV DNA at primary cervical carcinomas or at the lymph nodes (all P > 0.1). We conclude that, although detectable p53 protein is a common feature of cervical carcinomas, it is not predictive of metastases and is independent of HPV infection. J. Med. Virol. 53:111–117, 1997. © 1997 Wiley-Liss, Inc.     

Losses of heterozygosity on chromosomes 17p and 9p/18q my play important roles in early and advanced phases of gallbladder carcinogenesis

Purpose: This present study aimed to investigate the genetic changes in gallbladder carcinogenesis. Methods: Eleven intramucosal gallbladder carcinomas were compared with 31 invasive lesions for loss of heterozygosity (LOH) on chromosomes 5q, 9p, 17p and 18q, frame-shift mutations in a ten-adenine repeat site within the gene encoding the transforming growth factor β type II receptor (TGFβRII) and an eight-guanine repeat site within BAX, and point mutations in codon 12 of Ki-ras. Results: The incidences of LOH in intramucosal and invasive carcinomas were 14% and 17% on 5q, 9% and 52% on 9p, 64% and 65% on 17p, and 13% and 32% on 18q. No frame-shift mutations were found at TGFβRII or BAX, and point mutations in codon 12 of Ki-ras were present in only 8% of the samples. Thus, LOH on 17p was by far the most frequent lesion with similar results in both intramucosal and invasive carcinomas. In contrast, the frequency of LOH on 9p and 18q was distinctly higher in invasive lesions. Conclusion: The present data suggest that LOH on 17p may play an important role in the evolution of gallbladder carcinoma from a relatively early phase, while LOH on 9p and 18q may play roles in progression. Received: 9 December 1998 / Accepted: 12 February 1999     

大肠肿瘤p53蛋白过表达对原位Th1／Th2平衡的影响

目的：评价p53蛋白过表面对大肠腺瘤和大肠癌局部辅助T细胞（Th1/Th2)平均的影响,进而探讨大肠癌发生的免疫学机制,方法：研究对象包括大肠腺瘤30例,大肠癌38例,癌旁正常粘膜68例作为对照组。石蜡切片以免疫组化法检测p53蛋白表达,采用酶联免疫吸附试验（ELISA）检测肠组织培养上清液中4种细胞因子（IL－2,IL－4,IL－10,IFN－r)水平。结果：p53蛋白表达阳性组培养上清液的IL－2,IFN－r水平显著低于阴性组和对照组（P＜0．01）,而IL－10则高于阴性组及对照组（P＜0．05）,各组IL－4水平未显示差异（P＞0．05）,结论：p53蛋白表达引起原位Th1/Th2平衡失调,表现为由Th1向Th2漂移,初步推断：p53基因失活在大肠癌发生的免疫学机制中可能具有重要作用。     

Relation between K-ras codon 12 mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction

It is well known that the incidence of biliary cancer is higher in patients with pancreaticobiliary maljunction (PBM) than in individuals without PBM. However, the relationship between PBM and the carcinogenesis remains unclear. The purpose of the present study was to examine histopathologic changes in the mucosa of the gallbladder and bile duct in patients with PBM, and to investigate K‐ras oncogene mutation and overexpression of p53 protein in the mucosa. We examined 47 surgical specimens of gallbladder and 36 surgical specimens of bile duct obtained from 48 patients with PBM. The 48 patients were divided into three age groups: group A (0—3 years), group B (4—39 years), and group C (40 years or more). Investigation of K‐ras mutation and overexpression of p53 protein was performed using an enriched polymerase chain reaction (PCR) and enzyme‐linked mini‐sequence assay (ELMA), and by the streptavidin‐biotin (SAB) method, using DO‐7 antibodies, respectively. Hyperplastic changes in the gallbladder mucosa were observed in patients in the three groups. However, metaplastic or dysplastic changes were observed in the mucosa of only groups B and C. K‐ras gene mutation in the gallbladder mucosa was found in 18.8% of the hyperplastic mucosae in group B and in 20% in group C. The mutation was found in 33.3% of lesions with metaplastic change associated with hyperplastic changes and in 25% of lesions with dysplastic changes in group C. No mutation was observed in the non‐cancerous mucosae of gallbladders and bile ducts without congenital dilatation of the bile duct. Overexpression of p53 protein was observed only in carcinoma of the gallbladder; in seven of nine advanced carcinomas and in two of three carcinomas in situ. We concluded that the mucosal epithelia of the biliary system in patients with PBM showed a high frequency of gene mutations and the carcinogenesis appeared in involve a multistage process of mutation in the K‐ras gene and the p53 supressor gene.     

p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis.     

ASRGL1 downregulation suppresses hepatocellular carcinoma tumorigenesis in a CDK1-dependent manner

The asparaginase-like protein 1 (ASRGL1) catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia. Emerging evidences have shown a strong correlation between ASRGL1 expression and tumorigenesis. However, the expression and biological function of ASRGL1 in hepatocellular carcinoma (HCC) are still unclear. Here, we explored anti-tumor activity and fundamental mechanisms of ASRGL1 blockade in the HCC progression. Expression levels of ASRGL1 in patients with HCC were higher than those in the adjacent normal tissue. In addition, increased expression of ASRGL1 in HCC patients was correlated with poor overall survival. Knockdown of ASRGL1 gene in HepG2 and Li-7 cell lines inhibited cell proliferation, migration and invasion, but promoted apoptosis in vitro. ASRGL1 knockdown suppressed tumor growth in vivo. Conversely, ASRGL1 overexpression promoted cell proliferation, migration and invasion in HepG2 cells. Through bioinformatics analysis, we found that ASRGL1 might participate in the regulation of the cell cycle. Flow cytometry analysis conformed that ASRGL1 knockdown captured the cell cycle during the G2/M phase. ASRGL1 blockade promoted P53 protein expression and reduced expression of cyclin B and CDK1 proteins, as well as failed to binding. Moreover, CDK1 overexpression was able to reverse the decreased proliferation, migration and invasion of HepG2 cells induced by ASRGL1 knockdown. Collectively, our studies indicate that ASRGL1 blockade functions to inhibit cyclin B/CDK1-dependent cell cycle, leading to G2-to-M phase transition failure and tumor suppression in HCC.