The role of exosomes in hepatitis,liver cirrhosis and hepatocellular carcinoma

Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome‐mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome‐mediated biological processes.     

The role of EGF‐EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment

Epidermal growth factor (EGF) and their receptor (EGFR) play an important role in the development of cancer proliferation, and metastasis, although the mechanism remains unclear. The present study aimed at investigating the role of EGF‐EGFR signalling pathway in the development of human hepatocellular carcinoma (HCC) inflammatory environment. Gene profiles of inflammatory cytokines from HCC were measured. Cell bio‐behaviours of HCC with low or high metastasis were detected by the live cell monitoring system. Cell proliferation was measured by CCK8. The protein level of CXCL5 and CXCL8 was measured by ELISA. The phosphorylation of PI3K, ERK, MAPK was measured by western blot. EGF significantly induced cell proliferation in HepG2 cells, but not in HCCLM3 cells. EGF prompted the cell movement in both HepG2 and HCCLM3 and regulated the production of CXCL5 and CXCL8 from HCC, which were inhibited by EGFR inhibitor, Erk inhibitor (U0126), or PI3K inhibitors (BEZ‐235 and SHBM1009). HCC proliferation, metastasis and production of inflammatory cytokines were regulated via EGF‐EGFR signal pathways. CXCL5 could interact with CXCL8, possibly by CXCR2 or the cross‐talk between CXCR2 and EGFR. EGF‐EGFR signaling pathway can be the potential target of therapies for HCC.     

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

Epithelial–mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor‐associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N‐cadherin was down‐regulated and that of E‐cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF‐β1) and CAL27 similar to mesenchymal cells formed after TGF‐β1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor‐dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1‐positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN.     

Intracellular reduction in ATP levels contributes to CYT997‐induced suppression of metastasis of head and neck squamous carcinoma

The incidence rate of head and neck squamous cell carcinoma (HNSCC) has steadily increased over the past decade. However, treatment options for metastatic HNSCC are often limited and the 5‐year survival rate has remained static. Therefore, the development and assessment of more efficient but less toxic therapeutic strategies is an unmet need for treatment of more extensive HNSCC. Here, we report that CYT997, a novel microtubule‐disrupting agent, exerts strong activity in inhibiting HNSCC cell invasion and metastasis. The loss of invasion capacity by CYT997 was accompanied by an associated increase in cell adhesion and the reversal of epithelial‐mesenchymal transition (EMT). Increased expression of E‐cadherin protein and decreased expression of Vimentin protein became evident in HNSCC cells following CYT997 exposure, which were consistently observed in HNSCC xenografts from the mice receiving CYT997. Moreover, the capacity of invasive HNSCC cells to form pulmonary metastases was significantly blocked with CYT997 treatment, indicating that the diminishment of EMT traits contributes to CYT997‐suppressed metastasis. Intriguingly, CYT997 impaired intracellular ATP levels in HNSCC cells, at least in part, through its inhibitory effect on the mitochondrial protein IF1. The addition of ATP attenuated CYT997‐induced suppression of cell invasion, coupled with down‐regulation of E‐Cadherin and up‐regulation of Vimentin. These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT997. Collectively, our data unveil the mechanism involved in mediating CYT997 action, and provide preclinical rationale for possible clinical application of CYT997 as a novel therapeutic strategy against aggressive HNSCC.     

Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population

Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42–0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43–0.94) and non‐drinkers (OR = 0.79, 95% CI = 0.64–0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37–0.83) and non‐drinker (adjusted OR = 0.75, 95% CI = 0.60–0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene–gene interactions among three AKT1 SNPs (P < 0.015). A three‐AKT1 SNP haplotype (C‐A‐C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52–0.94). Multifactor dimensionality reduction analysis confirmed a high‐order gene–environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene–environment interplay in ESCC carcinogenesis.     

Mitochondria of a human multidrug‐resistant hepatocellular carcinoma cell line constitutively express inducible nitric oxide synthase in the inner membrane

Mitochondria play a crucial role in pathways of stress conditions. They can be transported from one cell to another, bringing their features to the cell where they are transported. It has been shown in cancer cells overexpressing multidrug resistance (MDR) that mitochondria express proteins involved in drug resistance such as P‐glycoprotein (P‐gp), breast cancer resistant protein and multiple resistance protein‐1. The MDR phenotype is associated with the constitutive expression of COX‐2 and iNOS, whereas celecoxib, a specific inhibitor of COX‐2 activity, reverses drug resistance of MDR cells by releasing cytochrome c from mitochondria. It is possible that COX‐2 and iNOS are also expressed in mitochondria of cancer cells overexpressing the MDR phenotype. This study involved experiments using the human HCC PLC/PRF/5 cell line with and without MDR phenotype and melanoma A375 cells that do not express the MDR1 phenotype but they do iNOS. Western blot analysis, confocal immunofluorescence and immune electron microscopy showed that iNOS is localized in mitochondria of MDR1‐positive cells, whereas COX‐2 is not. Low and moderate concentrations of celecoxib modulate the expression of iNOS and P‐gp in mitochondria of MDR cancer cells independently from inhibition of COX‐2 activity. However, A375 cells that express iNOS also in mitochondria, were not MDR1 positive. In conclusion, iNOS can be localized in mitochondria of HCC cells overexpressing MDR1 phenotype, however this phenomenon appears independent from the MDR1 phenotype occurrence. The presence of iNOS in mitochondria of human HCC cells phenotype probably concurs to a more aggressive behaviour of cancer cells.     

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

High‐grade serous ovarian carcinomas (HGSOCs) were among the tumours with an unsatisfactory outcome of immune checkpoint inhibitors (ICIs). It is imperative to develop feasible biomarker for identifying responsive candidates and guiding precise immunotherapy for HGSOC patients. Here, we analysed genomic data of patients with HGSOCs to depict their immunological phenotype of tumour microenvironment (TME) and figure out the major determinants of immunogenicity. In comparison with other solid tumours, we observed the lowest levels of PD‐L1, total mutation burden (TMB) and cytolytic molecules in HGSOCs. Surprisingly, TMB is not certainly positively related to tumour immune response as it failed to predict the response to ICIs in a considerable portion of patients in previous clinical trials. By a machine learning approach in search of biomarkers for immunotherapy implications for HGSOCs, we identified the ten most dominant factors determining the immunogenicity of HGSOCs. Interestingly, we found that BRCA1 mutated tumours presented a potent immunogenic phenotype, independent of TMB, meeting the criteria of both our dominant factors and the determinants of immunogenicity established before. Our findings provide evidence that BRCA1‐mutation may be served as a predictive biomarker in guiding ICI therapies for the patients with HGSOCs.     

Induction of p53‐independent growth inhibition in lung carcinoma cell A549 by gypenosides

The objectives of this study are to investigate antiproliferative effect and mechanisms of bioactive compounds from Gynostemma pentaphyllum (G. pentaphyllum) on lung carcinoma cell A549. Saponins, carotenoids and chlorophylls were extracted and fractionated by column chromatography, and were subjected to high‐performance liquid chromatography‐mass spectrometry analyses. The saponin fraction, which consisted mainly of gypenoside (Gyp) XXII and XXIII, rather than the carotenoid and chlorophyll ones, was effective in inhibiting A549 cell growth in a concentration‐ and a time‐dependent manner as evaluated using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The estimated half maximal inhibitory concentration (IC₅₀) of Gyp on A549 cells was 30.6 μg/ml. Gyp was further demonstrated to induce an apparent arrest of the A549 cell cycle at both the S phase and the G2/M phase, accompanied by a concentration‐ and a time‐dependent increase in the proportions of both the early and late apoptotic cells. Furthermore, Gyp down‐regulated cellular expression of cyclin A and B as well as BCL‐2, while up‐regulated the expression of BAX, DNA degradation factor 35 KD, poly [ADP‐ribose] polymerase 1, p53, p21 and caspase‐3. Nevertheless, both the treatment of a p53 inhibitor, pifithrin‐α, and the small hairpin RNA‐mediated p53 knockdown in the A549 cells did not alter the growth inhibition effect induced by Gyp. As a result, the cell cycle arrest and apoptosis of A549 cells induced by Gyp would most likely proceed through p53‐independent pathway(s).     

PI3K inhibition potentiates Bcl‐2‐dependent apoptosis in renal carcinoma cells

Inhibitors of PI3‐K/Akt are currently being assessed clinically in patients with advanced RCC. Identification of therapeutic strategies that might enhance the efficacy of PI3‐K/Akt inhibitors is therefore of great interest. As PI3‐K inhibition would be expected to have many pro‐apoptotic effects, we hypothesized that there may be unique synergy between PI3‐K inhibitors and BH3‐mimetics. Towards this end, we assessed the combination of the PI3K inhibitor LY 294002 and the Bcl‐2 family inhibitor ABT‐737 in RCC cell lines. We found that the combinatorial treatment with these agents led to a significant increase in PARP cleavage and cell death in all RCC cell lines. The synergized cell death was correlated with decreased levels of Mcl‐1 and XIAP, and increased levels in Bim, and appears critically dependent upon the activation of caspase 3 and 8. The enhanced lethality observed with the combination also appears dependent upon the regulation of XIAP, Mcl‐1 and Bim levels. Our results suggest that the combination of PI3‐K inhibitors with BH3‐mimetics may be a viable therapeutic strategy in RCC.     

Importance of PNO1 for growth and survival of urinary bladder carcinoma: Role in core‐regulatory circuitry

PNO1 (partner of Nob1) was known as a RNA‐binding protein in humans, and its ortholog PNO1 was reported to participate ribosome and proteasome biogenesis in yeasts. Yet there have been few studies about its functions in mammalian cells, and so far its role in human cells has never been reported, especially in urinary bladder cancer (UBC).We interrogated the cellular functions and clinical significance of PNO1 in, and its molecular mechanism through microarrays and bioinformatics analysis. Our findings support that PNO1 participates in promoting proliferation and colonogenesis, while reducing apoptosis of UBC cells, and is also predicted to be associated with the migration and metastasis of UBC PNO1 knockdown (KD) attenuated the tumorigenesis ability of UBC in mouse. PNO1 KD led to the altered expression of 1543 genes that are involved in a number of signalling pathways, biological functions and regulation networks. CD44, PTGS2, cyclin D1, CDK1, IL‐8, FRA1, as well as mTOR, p70 S6 kinase, p38 and Caspase‐3 proteins were all down‐regulated in PNO1 KD cells, suggesting the involvement of PNO1 in inflammatory responses, cell cycle regulation, chemotaxis, cell growth and proliferation, apoptosis, cell migration and invasiveness. This study will enhance our understanding of the molecular mechanism of UBC and may eventually provide novel targets for individualized cancer therapy.     

Enhanced NOLC1 promotes cell senescence and represses hepatocellular carcinoma cell proliferation by disturbing the organization of nucleolus

The nucleolus is a key organelle that is responsible for the synthesis of rRNA and assembly of ribosomal subunits, which is also the center of metabolic control because of the critical role of ribosomes in protein synthesis. Perturbations of rRNA biogenesis are closely related to cell senescence and tumor progression; however, the underlying molecular mechanisms are not well understood. Here, we report that cellular senescence‐inhibited gene (CSIG) knockdown up‐regulated NOLC1 by stabilizing the 5′UTR of NOLC1 mRNA, and elevated NOLC1 induced the retention of NOG1 in the nucleolus, which is responsible for rRNA processing. Besides, the expression of NOLC1 was negatively correlated with CSIG in the aged mouse tissue and replicative senescent 2BS cells, and the down‐regulation of NOLC1 could rescue CSIG knockdown‐induced 2BS senescence. Additionally, NOLC1 expression was decreased in human hepatocellular carcinoma (HCC) tissue, and the ectopic expression of NOLC1 repressed the proliferation of HCC cells and tumor growth in a HCC xenograft model.     

Identification of stably expressed reference small non‐coding RNAs for microRNA quantification in high‐grade serous ovarian carcinoma tissues

MicroRNAs (miRNAs) belong to a family of small non‐coding RNAs (sncRNAs) playing important roles in human carcinogenesis. Multiple investigations reported miRNAs aberrantly expressed in several cancers, including high‐grade serous ovarian carcinoma (HGS‐OvCa). Quantitative PCR is widely used in studies investigating miRNA expression and the identification of reliable endogenous controls is crucial for proper data normalization. In this study, we aimed to experimentally identify the most stable reference sncRNAs for normalization of miRNA qPCR expression data in HGS‐OvCa. Eleven putative reference sncRNAs for normalization (U6, SNORD48, miR‐92a‐3p, let‐7a‐5p, SNORD61, SNORD72, SNORD68, miR‐103a‐3p, miR‐423‐3p, miR‐191‐5p, miR‐16‐5p) were analysed on a total of 75 HGS‐OvCa and 30 normal tissues, using a highly specific qPCR. Both the normal tissues considered to initiate HGS‐OvCa malignant transformation, namely ovary and fallopian tube epithelia, were included in our study. Stability of candidate endogenous controls was evaluated using an equivalence test and validated by geNorm and NormFinder algorithms. Combining results from the three different statistical approaches, SNORD48 emerged as stably and equivalently expressed between malignant and normal tissues. Among malignant samples, considering groups based on residual tumour, miR‐191‐5p was identified as the most equivalent sncRNA. On the basis of our results, we support the use of SNORD48 as best reference sncRNA for relative quantification in miRNA expression studies between HGS‐OvCa and normal controls, including the first time both the normal tissues supposed to be HGS‐OvCa progenitors. In addition, we recommend miR‐191‐5p as best reference sncRNA in miRNA expression studies with prognostic intent on HGS‐OvCa tissues.     

PON1 hypermethylation is associated with progression of renal cell carcinoma

In this study, our aim was to exploring the influences of DNA methylation of PON1 on cell proliferation, migration and apoptosis of renal cancer cells. The genome‐wide methylation array of renal cell carcinoma samples and adjacent tissues were obtained from the cancer genome atlas (TCGA) database. By analysing the DNA methylation and conducting the CpG islands array, methylation status expressed in renal tumour samples and normal renal tissue samples were detected. Methylation‐specific PCR (MS‐PCR) and qRT‐PCR were employed to detect the methylation level and mRNA expression of PON1. Wound‐healing assay, transwell assay and MTT assay were utilized to detecting the migration, invasion and proliferation abilities, respectively. The cell apoptosis was testified by Tunnel assay. In addition, the effect of PON1 on renal cancer cells was verified by experiments in vivo. The methylation status of different genes in renal cell carcinoma samples was obtained by CpG islands arrays and hypermethylated PON1 was selected for further study. PON1 was down‐regulated in renal cell carcinoma tissues detected by qRT‐PCR and Western blot. Both in vitro and vivo experiments indicated that the sunitinib‐resistant in renal cancer cells could be suppressed by treat with 5‐Aza‐dC or TSA, and the effect came out more obvious after 5‐Aza‐dC and TSA co‐treatment. In detail, the demethylation of PON1 inhibited the migration, invasion and proliferation of renal cancer cells and also arrested more cells in G0/G1 phase. The vivo experiment indicated that demethylated PON1 suppressed the growth of tumour. Hypermethylated PON1 promoted migration, invasion and proliferation of sunitinib‐resistance renal cancer cells and arrested more cells in G0/G1 phase.     

LncRNA SNHG1 functions as a ceRNA to antagonize the effect of miR‐145a‐5p on the down‐regulation of NUAK1 in nasopharyngeal carcinoma cell

How lncRNA SNHG1 influences the aggressiveness of nasopharyngeal carcinoma cells as well as the underlying mechanism was studied. The lncRNA differences were analysed by GSE12452 gene microarray. The expression of SNHG1, MiR‐145‐5p and NUAK1 was identified by qRT‐PCR and western blot. Transfection was conducted to construct nasopharyngeal carcinoma cells with different expressions of SNHG1, miR‐145‐5p and NUAK1. Dual‐luciferase reporter assay was performed to explore the relationship between SNHG1, miR‐145‐5p and NUAK1. Wound‐healing assay and transwell invasion experiments were employed to study changes in cell migration capacity and cell invasion, respectively. Tumour xenografts were performed to observe lung metastasis of nude mice inoculated with transfected CNE cells. SNHG1 is highly expressed in nasopharyngeal carcinoma tissues and in cell lines. Down‐regulation of SNHG1 facilitated the expression of miR‐145‐5p and further suppressed the level of NAUK1 in CNE and HNE‐1 cells. Silencing of SNHG1, up‐regulation of miR‐145‐5p and inhibition of NAUK1 by relative transfection all attenuated the aggressiveness of CNE and HNE‐1 cells both in vivo and in vitro. Moreover, the impaired cell migration and invasion by SNHG1 siRNA could be rescued by cotransfection of miR‐145‐5p in CNE and HNE‐1 cells. LncRNA SNHG1 promoted the expression of NUAK1 by down‐regulating miR‐145‐5p and thus promoted the aggressiveness of nasopharyngeal carcinoma cells through AKT signalling pathway and induced epithelial‐mesenchymal transition (EMT).     

TMEM207 hinders the tumour suppressor function of WWOX in oral squamous cell carcinoma

The WW domain‐containing oxidoreductase (WWOX) functions as a tumour suppressor in oral carcinogenesis. As aberrant TMEM207 expression may lead to tumour progression by hampering the tumour suppressor function of WWOX in various cancers, we explored the expression and pathobiological properties of TMEM207, focusing on the WWOX‐mediated regulation of the HIF‐1α pathway in oral squamous cell carcinoma (OSCC). TMEM207 immunoreactivity was detected in 40 of 90 OSCC samples but not in neighbouring non‐tumorous epithelial tissues. Moreover, TMEM207 expression was significantly correlated with lymph node metastasis and poor prognosis. An in situ proximal ligation assay demonstrated the colocalization of TMEM207 and WWOX in invasive OSCC cells, especially glycogen‐rich ones. Enforced expression of TMEM207 abrogated the binding of WWOX to HIF‐1α, increased HIF‐1α and GLUT‐1 expression, even under normoxic conditions, and promoted tumour growth in a xenoplant assay using SAS tongue squamous cancer cells. In contrast, TMEM207 knockdown decreased GLUT‐1 expression in two OSCC cell lines. As a whole, our findings indicate that the aberrant expression of TMEM207 contributes to tumour progression in OSCC, possibly via promoting aerobic glycolysis.     

Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye, with a higher incidence documented in Haflinger horses. Recently, a missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses. SCC also occurs on the nictitating membrane; therefore, investigating the role of this missense variant in nictitating membrane SCC is warranted. In this study, a common ancestor was identified among Haflinger horses affected with limbal SCC or with nictitating membrane SCC, thus supporting a recessive risk factor for the development of cancer at both ocular locations. Analysis of genotype data from Haflinger horses with and without nictitating membrane SCC revealed that the same region on ECA12 associated with limbal SCC was also associated with nictitating membrane SCC (P < 2.04 × 10^?5). Fine mapping of this locus using 25 cases and 49 controls supported the hypothesis that DDB2:c.1013C>T, p.Thr338Met, is a risk factor for nictitating membrane SCC, as 88% of our cases were homozygous for this variant and no other polymorphism was more strongly associated (P = 4.13 × 10^?14). These data indicate that the genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses and validates utilization of genetic testing of the DDB2 variant for both clinical management and the guidance of mating decisions.     

MiR‐552 promotes the proliferation,migration and EMT of hepatocellular carcinoma cells by inhibiting AJAP1 expression

Our goal was to explore the function of miR‐552 and its potential target AJAP1 in hepatocellular carcinoma (HCC) oncogenesis and progression. In this study, bioinformatics analysis was performed to detect abnormally expressed miRNAs. The relationship between miR‐552 and AJAP1 was validated using luciferase reporter assays. RT‐qPCR and Western blot assays were applied to explore the expression level of miR‐552, AJAP1 and epithelial‐mesenchymal transition (EMT) markers. HCC cell proliferation was examined using CCK8 assays, while migration and invasion were investigated using Transwell assays. Nude mouse tumourigenesis models were established to facilitate observation of HCC progression in vivo. Finally, prognostic analysis was performed to discover how the prognosis of HCC patients correlated with miR‐552 and AJAP1 expression. MiR‐552 overexpression in HCC cells promoted HCC cell migration, invasion and EMT by targeting/suppressing AJAP1. Poorer prognosis appeared in HCC patients with higher miR‐552 expression or lower AJAP1 levels. Our findings suggested that miR‐552 promotes HCC oncogenesis and progression by inhibiting AJAP1 expression.