Characterization of the distinct immune microenvironments between hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

As two major types of primary liver cancers, the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have been well studied separately. However, a systemic assessment of the similarities and differences between the TIME of HCC and ICC is still lacking. In this study, we pictured a landscape of combined TIME of HCC and ICC by sequencing and integrating 41 single-cell RNA-seq samples from four different tissue types of both malignancies. We found that T cells in HCC tumors generally exhibit higher levels of immunosuppression and exhaustion than those in ICC tumors. Myeloid cells in HCC and ICC tumors also exhibit distinct phenotypes and may serve as a key factor driving the differences between their TIMEs. Besides, we identified a cluster of EGR1+ macrophages specifically enriched in HCC tumors. Together, our study provides new insights into cellular composition, states and interactions in the TIMEs of HCC and ICC, which could pave the way for the development of future therapeutic targets for liver cancers.

Malignant fibrous histiocytoma of the axilla with breast cancer: A case report.

BACKGROUND: Multiple primary malignant neoplasms refer to multiple tumors with different origins. They may be synchronous or metachronous. The incidence is 0.73%- 11.7%. Synchronous cases of breast cancer with sarcoma are rare. CASE SUMMARY: Here, we report a 78-year-old female patient admitted to hospital after accidental discovery of a left axillary mass. Preoperative examination revealed a breast mass. Pathology showed left breast cancer and left axillary sarcoma. The patient underwent surgery, endocrine therapy and radiotherapy. She has been followed up for 1 year, and no local recurrence or distant metastasis was observed. CONCLUSION: Attention should be paid to multiple primary malignant neoplasms, not limited to the current diagnosis and analysis, avoiding missed diagnosis and misdiagnosis.

A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. We show the enrichment of central memory T cells (TCM) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. We find the MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy.

Genomic gain of RRS1 promotes hepatocellular carcinoma through reducing the RPL11-MDM2-p53 signaling.

Hepatocellular carcinomas (HCCs) are characterized by frequent somatic genomic copy number alterations (CNAs), with most of them biologically unexplored. Here, we performed integrative analyses combining CNAs with the transcriptomic data to reveal the cis- and trans-effects of CNAs in HCC. We identified recurrent genomic gains of chromosome 8q, which exhibit strong trans-effects and are broadly associated with ribosome biogenesis activity. Furthermore, 8q gain-driven overexpression of ribosome biogenesis regulator (RRS1) promotes growth of HCC cells in vitro and in vivo. Mechanistically, RRS1 attenuates ribosomal stress through retaining RPL11 in the nucleolus, which, in turn, potentiates MDM2-mediated ubiquitination and degradation of p53. Clinically, higher RRS1 expression levels predict poor clinical outcomes for patients with HCC, especially in those with intact p53 Our findings established that the chromosome 8q oncogene RRS1 promotes HCC development through attenuating the RPL11-MDM2-p53 pathway and provided new potential targets for treatment of this malignancy.

Downregulation of ZC3H14 driven by chromosome 14q31 deletion promotes hepatocellular carcinoma progression by activating integrin signaling.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Genomic copy number deletion at chromosome 14q31.1-32.13 was frequently observed in HCC; however, the relevant functional target(s) at that locus is not well determined. Here, we performed integrative genomic analyses and identified zinc finger CCCH-type containing 14 (ZC3H14) as a promising candidate at 14q31.1-32.13. We observed frequent copy number deletion (17.1%) and downregulation of ZC3H14 in primary HCC tissues. Downregulation of ZC3H14 was significantly associated with poor outcomes of patients with HCC. Overexpression of ZC3H14 in HCC cell lines significantly suppressed HCC cells growth in vitro and metastasis in vivo. In contrast, RNA interference silencing of ZC3H14 inhibited its tumor-suppressive function. Mechanismly, through combing bioinformatics analyses and experimental investigation, we demonstrated that loss of ZC3H14 promotes HCC progression through enhancing integrin pathway. This study suggests that ZC3H14 functions as a novel tumor suppressor and is a candidate prognostic biomarker for HCC patients.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

Genome-Wide Association Study Identifies a New Locus at 7q21.13 Associated with Hepatitis B Virus-Related Hepatocellular Carcinoma.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC.Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls.Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 × 10-10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients.Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906-15. ©2017 AACR.

Anticancer activity of bicalutamide-loaded PLGA nanoparticles in prostate cancers.

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in men in western and most developing countries. Bicalutamide (BLT) is an antineoplastic hormonal agent primarily used in the treatment of locally advanced and metastatic prostate cancers. In the present study, the aim was to develop a nanotechnology-based delivery system to target prostate cancer cells. This involved the development of a BLT-loaded poly(D,L-lactide-co-glycolide) PLGA (PLGA-BLT) nanoparticulate system in an attempt to improve the therapeutic efficacy of BLT in prostate cancer and to mitigate its toxicity. Nanosized particles with a uniform size distribution and spherical shape were developed. PLGA-BLT showed a pronounced cytotoxic effect on LNCaP and C4-2 cancer cells. The superior cell-killing effect of the nanoparticles may be attributable to their sustained drug-release characteristics and high cellular internalization. PLGA-BLT was also found to significantly inhibit colony formation in the two cell lines. Furthermore, the caspase-3 activity of PLGA-BLT treated cancer cells was enhanced, indicating the cell apoptosis-inducing potential of PLGA-BLT. Overall, these results suggest that nanotechnology-based formulations of BLT exhibit superior anticancer activity and have enormous potential in the treatment of prostate cancers.

Prognostic impact of NDRG2 and NDRG3 in prostate cancer patients undergoing radical prostatectomy.

AIM: To investigate the clinicopathologic significance of NDRG2 and NDRG3, and their involvement in recurrence-free survival (RFS) and overall survival (OS) of prostate cancer (PCa). METHODS: NDRG2 and NDRG3 expression in 206 pairs of primary PCa and corresponding noncancerous prostate tissue samples from the same specimens were detected by immunohistochemistry. The association of NDRG2 and NDRG3 expression with the clinicopathologic features and with the prognosis of PCa was subsequently assessed. RESULTS: In PCa tissues, NDRG2 expression was significantly downregulated, while NDRG3 expression was significantly upregulated (both P<0.001), compared with those in corresponding noncancerous prostate tissues. In addition, the downregulation of NDRG2 in PCa tissues was significantly correlated with advanced pathological stage (P=0.001), positive metastatic status (P=0.001) and high Gleason score (P=0.003), while the upregulation of NDRG3 in PCa tissues was significantly correlated with advanced pathological stage (P=0.006), positive metastatic status (P=0.001) and lymph node status (P=0.002). Furthermore, multivariate survival analysis showed low NDRG2 and high NDRG3 immunoreactivities were both significantly associated with short RFS and short OS in PCa independently of routine clinicopathological predictors. CONCLUSION: Our data offer convincing evidence for the first time that the aberrant expression of NDRG2 and NDRG3 may contribute to the malignant progression of PCa. More importantly, both the downregulation of NDRG2 and the upregulation of NDRG3 may be efficient prognostic indicators for PCa.

[Effects of soy bean isoflavone on inhibition of benign prostatic hyperplasia and the expressions of NO and NOS of rats].

OBJECTIVE: To explore the inhibitive effect of soybean isoflavone on the prostatic hyperplasia on the expressions of nitric oxid and nitric oxide synthase in the prostatic hyperplasia rats. METHODS: Subcutaneously injected testosterone propionate were to induce prostate hyperplasia in rats. The changes of prostate wet weight, prostatic index, liver index, the changes of some biochemical indexes in rat prostate tissue in the control and the treatment, the low, moderate, high dose groups of soybean isoflavone groups were observed. RESULTS: The prostate wet weight and prostatic index in all dose groups were merely lower than those in the treatment and the moderate groups were lowest in all dose group. There were no significant differences in liver index, urea nitrogen, glutamic-pyruvic transaminase of each group. Acid phosphatase, prostatic acid phosphatase and lactate dehydrogenase in all dose groups were merely lower than those in the treatment group. Nitric oxide and nitric oxide synthase in all dose groups were merely higher than those in the treatment group. CONCLUSION: Soybean isoflavone could inhibit prostate hyperplasia and increase the expressions of nitric oxide and nitric oxide synthase in rats.