KAI1 Expression Research Articles

Impact of Neuron-Derived HGF on c-Met and KAI-1 in CNS Glial Cells: Implications for Multiple Sclerosis Pathology.

Demyelination and axonal degeneration are fundamental pathological characteristics of multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS). Although the molecular mechanisms driving these processes are not fully understood, hepatocyte growth factor (HGF) has emerged as a potential regulator of neuroinflammation and tissue protection in MS. Elevated HGF levels have been reported in MS patients receiving immunomodulatory therapy, indicating its relevance in disease modulation. This study investigated HGF's neuroprotective effects using transgenic mice that overexpressed HGF. The experimental autoimmune encephalomyelitis (EAE) model, which mimics MS pathology, was employed to assess demyelination and axonal damage in the CNS. HGF transgenic mice showed delayed EAE progression, with reduced CNS inflammation, decreased demyelination, and limited axonal degeneration. Scanning electron microscopy confirmed the preservation of myelin and axonal integrity in these mice. In addition, we explored HGF's effects using a cuprizone-induced demyelination model, which operates independently of the immune system. HGF transgenic mice exhibited significant protection against demyelination in this model as well. We also investigated the expression of key HGF receptors, particularly c-Met and KAI-1. While c-Met, which is associated with increased inflammation, was upregulated in EAE, its expression was significantly reduced in HGF transgenic mice, correlating with decreased neuroinflammation. Conversely, KAI-1, which has been linked to axonal protection and stability, showed enhanced expression in HGF transgenic mice, suggesting a protective mechanism against axonal degeneration. These findings underscore HGF's potential in preserving CNS structure and function, suggesting it may be a promising therapeutic target for MS, offering new hope for mitigating disease progression and enhancing neuroprotection.

Combined dandelion extract and all-trans retinoic acid induces cytotoxicity in human breast cancer cells

Breast cancer is one of the most prevalent and deadly cancers among women worldwide. Recently, natural compounds have been widely used for the treatment of breast cancer. Present study evaluated antiproliferative and anti-metastasis activities of two natural compounds of dandelion and all-trans-retinoic acid (ATRA) in human MCF-7 and MDA-MB231 breast cancer cells. We also evaluated the expression of MMP-2, MMP-9, IL-1β, p53, NM23 and KAI1 genes. Data showed a clear additive cytotoxic effect in concentrations of 40 μM ATRA with 1.5 and 4 mg/ml of dandelion extract in MCF-7 and MDA-MB231 cells, respectively. In both cell lines, compared with the untreated cells, the expression levels of MMP-9 and IL-1β were significantly decreased while p53 and KAI1 expression levels were increased. Besides, MMP-2 and NM23 had different expressions in the two studied cell lines. In conclusion, dandelion/ATRA co-treatment, in addition to having strong cytotoxic effects, has putative effects on the expression of anti-metastatic genes in both breast cancer cells.

MiRNA-633 and KAI1 as Potential Biomarkers of Malignant Melanoma with Gastric Cancer.

Malignant melanoma with gastric cancer is one of the most malignant tumors. However, there have been no reports on the effects of KAI1 and miRNA-633 on the survival and prognosis of patients with malignant melanoma with gastric cancer. Fifty patients with malignant melanoma and gastric cancer were collected from October 2017 to December 2019. The clinical parameters included clinical information, such as sex, age, tumor size, and tumor staging. RT-qPCR was used to detect the expression of KAI1 and miRNA- 633. The role of KAI1 and miRNA-633 on the overall survival of melanoma was explored by the Pearson chi-square test, Spearman-rho correlation test, Univariate and multivariate cox regression analyses, and Kaplan-Meier method. Furthermore, the bioinformatic analysis was used to verify the role of KAI1 and miRNA-633 on malignant melanoma with gastric cancer. The expression of KAI1 and miRNA-633 was significantly related with the tumor size and staging of tumor (p<0.05) based on the Pearson chi-square test. Spearman's correlation coefficient displayed that KAI1 was significantly correlated with the miRNA-633 (ρ=-0.439, p=0.001). The result of multivariate cox proportional regression analysis showed that KAI1 (HR =0.109, 95% CI: 0.031-0.375, p< 0.001), and miRNA-633 (HR = 13.315, 95% CI: 3.844-46.119, p<0.001) were significantly associated with overall survival. The low expression level of KAI1 and high expression of miRNA-633 are significantly correlated with the poor overall survival prognosis of malignant melanoma with gastric cancer, to provide a basis for KAI1 and miRNA-633 to become novel molecular targets for malignant melanoma with gastric cancer.

Expression of KAI1 and AGR2 in lung adenocarcinoma and their clinicopathological significance

Anticancer 1 (KAI1, tumor metastasis suppressor gene) and Anterior gradient-2 (AGR2, considered a valuable prognostic factor for some cancers) are associated with metastasis and prognosis of various types of human cancers. Nevertheless, the relationship between KAI1 and AGR2 in lung adenocarcinoma (LUAD) remains unclear. In this research, we analyzed the correlations between KAI1 and AGR2 in LUAD, and explored their correlations with clinicopathological parameters and overall survival time (OS) in patients with LUAD. Immunohistochemical staining was used to detect KAI1 and AGR2 expression in 132 cases of LUAD samples. At the same time, all clinicopathological parameters and postoperative survival information were collected. AGR2 positive rate was significantly increased and KAI1 positive rate was significantly decreased in LUAD and control tissues. KAI1 positive rates were negatively correlated with tumor stage, LNM stage and TNM stage, and KAI1 subgroup positive expression of OS was significantly higher than negative KAI1 subgroup. The positive rate of AGR2 was positively correlated with tumor grade, LNM stage and TNM stage, and negatively correlated with patients OS. Active expression of AGR2 and KAI1, tumor stage, and LNM stage in multivariate analyses may be independent prognostic factors for OS in LUAD patients. KAI1 and AGR2 may be potential biomarkers for prognosis and metastasis, and they are also promising therapeutic targets for LUAD patients.

Lower expression of KAI1 as a biomarker of poor survival prognosis of melanoma combined with colorectal cancer metastasis.

ObjectiveThis study aimed to investigate the correlation between KAI1 (CD82) and miR-633 expression and prognosis and survival time of patients with melanoma combined with colorectal cancer (CRC).MethodsClinical and follow-up data of melanoma and CRC patients were recorded, and the expression levels of KAI1 and miR-633 were detected. Pearson chi-square tests and Spearman correlation coefficient were used to analyze the relationship between prognosis and related parameters in these patients. Cox proportional risk regression and receiver operating characteristic curve analyses were used.ResultsOverall, 195 patients were included. KAI1 and miR-633 expression levels were significantly correlated with the prognosis of patients with melanoma combined with CRC. Spearman correlation analysis showed that the expression levels of KAI1 and miR-633 were significantly correlated with the prognosis of patients. Multivariate Cox regression analysis suggested that low expression levels of KAI1 and high expression levels of miR-633 indicated shorter survival time for patients.ConclusionsKAI1 expression was significantly correlated with melanoma and CRC patient prognosis. When KAI1 expression levels were low, the patient survival time was poor.

The Cytotoxic Effect of Estradiol Valerate, Progesterone, and Testosterone on Brain Glioblastoma (A172) , Colorectal Cancer (HT29) and Human Embryonic Kidney (HEK293) Cells and the Expression Levels of Bax, Bcl-2, and KAI-1/CD82 in A172 and HT29 cells

Although the anticancer effects of sex steroids have been widely reported, the results are still controversial. This study investigated the cytotoxic effects of testosterone (T), estradiol (E), and progesterone (P) on A172, HT29, and HEK293 cells and the expression levels of Bax, Bcl-2, and CD82/KAI-1 in A172 and HT29 cells. Cell lines were divided into control groups and groups treated with 0.001, 0.01, 0.1, 1, and 10 mg/ml of T, P, and E valerate. The cytotoxic effect was measured using an MTT assay. 0.1 mg/ml of T, 0.1 mg/ml of P, and 0.1 mg/ml of E were used to evaluate the expression levels of Bax, Bcl-2, and KAI-1 genes using real-time PCR. One-way analysis of variance was used to analyze the data. Treatment with higher concentrations of T, E, and P led to decreased cell viability in Hek293 and HT29 cells. Treatment of A172 cells with higher concentrations of T, and of P led to decreased cell viability. Bax expression level increased in HT29 and A172 cells treated with T, and P. The expression level of the Bcl-2 decreased in HT29 cells treated with T, and P, and in A172 cells treated with P. Treatment of A172 cells with T, P, and E decreased KAI-1 expression level. Despite estradiol, testosterone and progesterone having cytotoxic effects on colon cancer and brain glioblastoma cells through the Bax gene-dependent apoptosis pathway. Estradiol and progesterone may have anti-metastatic effects on colon cancer cells.

In vitro anticancer effects of ibuprofen on HeLa cell line

Several studies have reported the anticancer effects of ibuprofen on cervical cancer cells, but the molecular pathway is still unclear in many aspects. This study aimed to investigate the effects of cytotoxic dose of ibuprofen on BAX, BCL-2, caspase-3, MMP-9, KAI-1 and NM23 gene expression levels and evaluation of caspase-3, -8 and -9 activity level in cervical cancer (HeLa) cells. Cervical cancer cells were divided into untreated (control) groups and ibuprofen treated groups. Expression levels of BAX, BCL-2, caspase-3, MMP-9, KAI-1 and NM23 genes were evaluated by Real-time PCR and caspase-3, -8 and -9 activity levels were determined using colorimetric method. Hoechst staining was used to confirm apoptosis. The data were statistically analyzed between groups using ANOVA and independent t-test. Significant increase in expression levels of caspases-3, and BAX/BCL-2 ratio, caspase-3, -8 and -9 activity level and a significant decrease in NM23, KAI-1 genes expression level were observed in HeLa cells treated with ibuprofen cytotoxic concentration. The apoptosis observed in HeLa cells was confirmed by Hoechst 333285 staining and flow cytometry analysis. Ibuprofen increased nuclear condensation and induced apoptosis in HeLa cells by both intrinsic and extrinsic apoptosis pathways.

EVALUATION OF CD82/ (KAI-1) IMMUNOHISTOCHEMICAL EXPRESSION IN COLORECTAL CARCINOMA

Background: Colorectal carcinoma (CRC) is one of the most common human cancers. It is the fourth most common cause of death from cancer. Colorectal cancer is the third most common cancer in men and the second in women worldwide. Objective: To evaluate the immunohistochemical expression of KAI-1/CD82 in different stages of colorectal carcinoma and to evaluate the biological behavior of tumor and target therapy. Patients and Methods: Thirty formalin-fixed, paraffin-embedded tissue of colorectal carcinoma (obtained from archive of Al-Azhar University Hospital Labs and some private labs). Clinicopathological and histological features were taken from files and confirmed by H&E examination. Immunohistochemical study was done by using CD82/ (KAI-1) marker. Results: CD82 showed an insignificant relation with age, sex, site of tumor and degree of differentiation. A significant inverse relationship was detected between CD82 expression in tumor cells and tumor stage according to modified Duke's staging. Insignificant relation between age, sex, site and grade. Conclusion: The decreased membranous and/or cytoplasmic expression of CD82 might be used as a prognostic marker to monitor patient with colorectal cancer.

Evaluation of Metastasis Suppressor Genes Expression and In Vitro Anti-Cancer Effects of Zinc Oxide Nanoparticles in Human Breast Cancer Cell Lines MCF-7 and T47D.

Background:Metallic nanoparticles are useful materials to be applied in biomedical research. In this study, the possible apoptotic and anti-metastatic activity of Zinc Oxide Nanoparticles (ZnONPs) was assessed in breast cancer cells.Methods:First, in vitro cell viability was investigated by MTT assay in two human breast cancer cells (MCF-7 and T47D) and normal Human Embryonic Kidney (HEK293) cells at 37°C overnight. Apoptosis induced by ZnONPs was evaluated by annexin V/PI staining, cell cycle analysis and caspase assay in cancerous cells. Moreover, quantitative real-time PCR was employed for the detection of two metastasis suppressor genes (KAI-1 and NM23) expression in cancerous cells.Results:Data demonstrated that ZnONPs exert a dose-dependent inhibitory effect on the viability of T47D and MCF-7 cells, while no cytotoxic effect was observed on normal HEK293 cells. The mRNA expression levels of KAI-1 and non-metastatic protein (NM23) genes were up-regulated in ZnONP-exposed cancerous cells. ZnONPs were also found to enhance the apoptosis properties of cells by annexin V/PI staining, and caspase assay in cancerous cells. Furthermore, ZnONPs can increase sub-G1 population as compared to negative control.Conclusion:Our findings showed that ZnONPs induce apoptotic activity and can modulate metastasis by up-regulating of KAI-1 and NM23 gene expression in two breast cancer (MCF-7 and T47D) cells.

Investigations of a Possible Role of SNPs in KAI1 Gene on Its Down-Regulation in Breast Cancer.

Objective: KAI1 (CD82) is a metastasis suppressor gene known to be down-regulated in carcinomas of breast, prostate and many other organs. The mechanism of KAI1 down-regulation is complex and not well understood. Here, we investigate the role of 8 SNPs (not previously studied) in KAI1 gene that could influence its expression in tumor tissue samples of breast cancer patients from the Eastern province of Saudi Arabia. Methods:Single nucleotide polymorphisms (SNPs) in KAI1 gene were selected from the NCBI website (dbSNP) and were then filtered for those SNPs causing stop codon mutations (rs139889503 and rs150533529) or nonsynonymous mutation in the 5’-UTR (rs11541048, rs77359459, rs115500759, rs182579675, rs200238062, and rs372733853). SNPs genotyping was performed using TaqMan SNP Genotyping Assay and the results were correlated with KAI1 protein expression profile by immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) samples of breast cancer and control none-neoplastic tissues. Results: KAI1 expression by IHC was observed in all none-neoplastic breast tissue samples and only in 35% out of the 59 breast cancer tissue samples. None of the samples was homozygous for the stop codon allele A in the SNP rs139889503 or allele T in the SNP rs150533529. The SNPs in the 5-UTR, rs11541048, rs115500759, and rs182579675, were only present in the homozygous state for the G and C alleles respectively in both cancer and control samples. The other SNPs in the 5’-UTR (rs77359459, rs200238062, and rs372733853) had no significant difference in the allele distribution between KAI1 expressing or none-expressing tissue samples. Conclusion:Our findings showed no significant effect of the studied SNPs on down-regulation of KAI1 expression.

Down Regulation of KAI1/CD82 in Lymph Node Positive and Advanced T-Stage Group in Breast Cancer Patients.

Background:Metastasis represents a deadly aspect of any cancer including breast cancer, given its high prevalence; treatment of metastatic breast cancer remains a clinically unmet need, which necessitates the exploration of metastasis suppressor genes (MSGs). KAI-1/CD82 is an important member of MSGs; the role of KAI1 has been well explored in prostate cancer, however its role in breast cancer is not fully explored and in fact the results of breast cancer studies are contentious. Thus, the present study aimed to investigate expression of KAI1 at both transcriptional and translational levels in the tissue of breast cancer patients and benign breast disease. Further, we analysed the relationship between expression levels of KAI1 and clinicopathological parameters in breast cancer patients. Materials and Methods: mRNA expression was studied by Real time PCR and protein expression was analyzed by both Western blot and Immunohistochemistry. Results:The results of the study indicate that KAI1 expression was remarkably decreased in breast cancer both at the gene and the protein levels (P < 0.05) compared to benign breast disease. In addition, KAI1 expression levels were strongly associated with axillary lymph node status and advanced T stage (p < 0.05), however no association was found with tumor grade, age, menopausal status and receptor status like ER, PR and Her2. Conclusion:Low expression of KAI1 might be helpful for predicting the lymph node metastasis and T staging, thus predicts malignant prognosis of breast cancer.

Alternative splicing is an important mechanism behind KAI1 loss of function in breast cancer patients from Saudi Arabia.

KAI1 (also called CD82) is a metastasis suppressor gene known to be downregulated in breast cancer and other solid tumors. The downregulation of KAI1 or loss of its function is usually associated with bad prognosis. The mechanism behind KAI1 loss of function is complex. In this study, we investigated "alternative splicing" as a possible mechanism that underlies KAI1 loss of function in breast cancer patients from a tertiary hospital in Saudi Arabia. Expression of KAI1 was studied in FFPE breast cancer and control tissue sections by IHC using two different antibodies targeting different domains of the protein. The TS82B antibody targets the extracellular loop, which constitutes most of the protein, while the second EPR4112 antibody targets the C-terminal intracellular domain of the protein. Out of 90 breast cancer samples, 67% showed loss of KAI1 expression. The remaining 33% showed KAI1 expression with (TS82B) antibody; however, the protein was detected in only 11% of cancers when using the antibody (EPR4112) indicating a truncation of the protein at the C-terminus (truncated-KAI1) in 22% of the studied cancer samples. A significant correlation was found between truncated-KAI1 expression and advanced cancer stage (association with lymph node metastasis, P value 0.008). Alternative splicing is an important mechanism underlying KAI1 loss of function in breast cancer, and it is associated with bad prognosis (advanced cancer stage).

Physciosporin suppresses the proliferation, motility and tumourigenesis of colorectal cancer cells

BackgroundLichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms. PurposeThe present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells. MethodsPHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo. ResultsPHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity. ConclusionPHY suppresses the growth and motility of CRC cells via novel mechanisms.

Expressions of KAI1 and E-cadherin in nonsmall cell lung cancer and their correlation with vasculogenic mimicry.

Background:Metastasis and recurrence are the most common reasons for treatment failure of nonsmall cell lung cancer (NSCLC). Vasculogenic mimicry (VM, new blood supply formation in malignant tumors), E-Cadherin (a calcium-dependent transmembrane glycoprotein that mediates intercellular adhesion), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse common human cancers. However, the correlation of VM, E-Cadherin, and KAI1 in NSCLC is still unclear. In this study, we analyzed the correlations among these factors as well as their respective correlations with clinicopathological parameters and survival in NSCLC.Methods:The level of VM, E-Cadherin, and KAI1 in 163 tissue samples of NSCLC was examined by immunhistochemistry. Clinical data were also collected.Results:Levels of VM was significantly higher, and levels of KAI1 and E-Cadherin significantly lower in NSCLC tissues than in normal lung tissues. Levels of VM were positively associated with lymph node metastasis (LNM), size, grade, and tumor node metastasis (TNM) stages, and negatively associated with patients’ overall survival (OS). Levels of KAI1 and E-Cadherin were negatively correlated with LNM, size, grade, and TNM stage, and positively associated with patients’ OS. In multivariate analysis, high levels of VM, E-Cadherin, and KAI1, as well as TNM stages were independently correlated with lower OS in patients with NSCLC.Conclusion:VM and the expression of E-Cadherin and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for NSCLC.

The role of miR-99b in mediating hepatocellular carcinoma invasion and migration.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults with a high rate of malignancy. The potent invasion and migration of HCC mainly impact the prognosis and recurrence of the disease. Our previous study found that miR-99b was highly expressed in HCC, and its expression was associated with vascular invasion. It was speculated that miR-99b may play a role in HCC invasion and migration, while the specific mechanism remains unclear. qRT-PCR was applied to detect expressions of miR-99b and KAI1 genes in L02, HepG2, and MHCC97H cells. HepG2 cells were transfected with miR-99b inhibitor, miR-99b mimic, and NC. Flow cytometry was used to test cell cycle and apoptosis. Dual-luciferase reporter gene assay was adopted to validate the target gene of miR-99b. Wound healing assay was used to detect cell migration. Transwell assay was performed to detect cell invasion. Western blot was performed to detect KAI1, E-cadherin, and N-cadherin expressions. Immunofluorescence assay was adopted to test Vimentin expression. The level of miR-99b was reduced in L02 while up-regulated in MHCC97H. By contrast, the expression of KAI1 was increased in L02 but declined in MHCC97H. The transfection of miR-99b mimic inhibited HepG2 apoptosis and accelerated cell cycle. MiR-99b suppressed KAI gene expression through targeting its 3'-UTR. MiR-99b mimic or si-KAI1 transfection promoted cell invasion and migration, while their simultaneous action significantly enhanced cell invasion and migration. The overexpression of miR-99b or knockdown of KAI1 significantly weakened HepG2 cell adhesion, reduced E-cadherin expression, upregulated N-cadherin and Vimentin, and promoted cell epithelial-mesenchymal transition (EMT). MiR-99b contributes to promoting function in HCC migration and invasion through inhibiting KAI1 expression.

KAI-1 ad p53 Expression in Odontogenic Cysts: An Immunohistochemical Marker Study

Background: KAI-1/CD82 is a tumor suppressor gene with decreased gene expression being associated with increased invasive ability of oral squamous cell carcinoma and as hypothesized for various odontogenic cysts and tumors. p53 protein functions in G1-S phase of the cell cycle to allow the repair of damaged DNA. In the present study, p53 and KAI-1 expression was investigated using monoclonal antibodies in the various odontogenic cysts. Aims: To detect KAI-1 and p53 expression in radicular cysts, dentigerous cysts, and odontogenic keratocysts (OKCs) and to assess the relation between p53 and KAI-1 expression in the aforementioned cysts. Materials and Methods: The present study included histopathologically diagnosed cases of radicular cysts, dentigerous cysts, and OKCs for the expression of KAI-1 and p53 antibodies. Results: Among odontogenic cysts, radicular cysts expressed maximum positivity of KAI-1 (20.92%) while p53-positive cells were maximum in OKC (4.04%). The correlation between KAI-1 and p53 expression in the various odontogenic cysts was not found to be significant. Conclusion: The increased KAI-1 expression in the radicular cysts and its downregulation in OKCs may be indicative of aggressive clinical behavior and the fact that OKCs are hypothesized as neoplastic rather than being developmental in origin.

TAp73 inhibits cell invasion and migration by directly activating KAI1 expression in colorectal carcinoma

p73 is a member of the p53 family of transcription factors and, like p53, plays a role as a tumor suppressor. p73 is involved in development, proliferation, apoptosis and metastasis. However, the precise molecular mechanisms underlying its function in inhibiting metastasis remain largely unknown. Here, we show that induction of TAp73 decreased invasion and migration activity of colorectal cancer cells, whereas knockdown of TAp73 led to increased invasion and migration activity. KAI1 was identified as a transcriptional target of TAp73 and its expression is indispensable for TAp73-mediated inhibition of cell invasion and migration. Furthermore, induction of TAp73 in colorectal cancer cells elevated KAI1 expression and decreased the frequency of hepatic metastasis in vivo. Whereas, the decreased invasion and migration activities caused by TAp73 induction were abrogated by knockdown of KAI1. Interestingly, TAp73 and KAI1 are overexpressed in primary colorectal cancers and a significant correlation between TAp73 and KAI1 expression was detected, but their expressions were significantly down-regulated in metastatic cancers. Taken together, our results support a novel role for TAp73 in controlling colorectal cancer cell invasion, migration and metastasis by regulating transcription of KAI1.

Roles of KAI1 and nm23 in lymphangiogenesis and lymph metastasis of laryngeal squamous cell carcinoma

BackgroundLymphatic metastasis contributes to the poor prognosis of laryngeal squamous cell carcinoma (LSCC). This study aimed to investigate the roles of two metastasis suppressor genes, KAI1 and nm23, in lymphangiogenesis and lymph metastasis of LSCC.MethodsA total of 45 LSCC patients were enrolled in this study. The positive expression rates of KAI1 and nm23 protein were detected via immunohistochemistry in 45 LSCC and 22 normal laryngeal mucosa adjacent to LSCC. Micro-lymphatic vessel density (MLVD) was detected via immunohistochemistry with the specific antibody D2-40. Associations between KAI1 and nm23 expression and clinical characteristics of LSCC were then evaluated.ResultsThe positive expression rates of KAI1 and nm23 were significantly lower in LSCC than normal laryngeal mucosa (P < 0.05). Significantly lower positive rates of KAI1 and nm23 were found in LSCC with lymphatic metastasis than those without lymphatic metastasis (P < 0.05), whereas MLVD was negatively correlated with the expression of KAI1 and nm23 (P < 0.05). However, no significant associations were found between KAI1 and nm23 expression and clinical characteristics of LSCC (sex, age, disease position, differentiation, and T-stage).ConclusionsBoth KAI1 and nm23 can inhibit lymphangiogenesis and lymphatic metastasis in LSCC.

Abstract 1879: Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis

Abstract Background: p73 is a member of the p53 family transcription factors and known tumor suppressor. However, its transcriptional activity is complex owing to its multiple isoforms, and limited information is available regarding the transcriptional and functional regulation of the p73 gene in colorectal cancer. In this study, we examined the role of p73 in colorectal cancer. Methods: We established a TAp73 overexpressing cell line using the Tet-on inducible expression system and analyzed global RNA expression by RNA-sequencing (RNA-seq). We studied the effects of TAp73 expression on the migration, invasiveness, and EMT of colon cancer cells. We conducted experiments in animals with liver metastasis of colorectal cancer. To investigate the roles of p73 in colon cancer, we examined the samples from patients, who had undergone surgical resection for colorectal cancer between 2009 and 2013. mRNA expression of TAp73 and KAI1 was analyzed in 108 colorectal cancer specimen and adjacent non-cancerous tissues by real-time RT-PCR. Results: RNA-seq showed the association between TAp73 and KAI1 expression. Migration and invasiveness of colon cancer cells were reduced by TAp73 expression, but induced by KAI1 knockdown. TAp73 regulates KAI1 expression in colon cancer cell lines. TAp73-induced decrease in invasiveness and epithelial-mesenchymal transition (EMT) was abrogated by KAI1 knockdown in TAp73 overexpressing cells. Migration ability of TAp73 overexpressing cells was recovered by KAI1 knockdown. Hepatic metastases were significantly reduced in mice injected with TAp73 overexpressing cells and increased in those injected with TAp73 overexpressing cells with KAI1 knockdown. mRNA expression of TAp73 and KAI1 was higher in colorectal cancer tissues than in adjacent non-cancerous tissues. Significant correlation between TAp73 and KAI1 mRNA expression was detected in early stage primary colorectal cancer, but not in the advanced stage. Conclusions: This study suggests that p73 (TAp73) acts as a tumor suppressor in the progression of colorectal cancer and regulates the expression of KAI1, which is a key target of p73 in colorectal cancer liver metastases. Note: This abstract was not presented at the meeting. Citation Format: Woo Kyun Bae, Kyung Hyun Yoo, Keunsoo Kang, Lothar Hennighausen, Ik-Joo Chung. Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1879. doi:10.1158/1538-7445.AM2017-1879

Evaluation of the correlation of vasculogenic mimicry, ALDH1, KAI1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma

BackgroundMetastasis and recurrence are the most common reasons for treatment failure of colorectal carcinoma (CRC). Vasculogenic mimicry (VM, blood supply formation often seen in highly aggressive tumors), Aldehyde dehydrogenase 1 (ALDH1, a biomarker of cancer stem cells), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse human cancers. However, the correlation of VM, ALDH1, KAI1 and microvessel density (MVD) in CRC is unclear. In this study, we analyzed the correlations among VM, ALDH1, KAI1 and MVD, as well as their respective correlations with clinicopathological parameters and survival in CRC.MethodsThe level of VM, ALDH1, KAI1 and MVD in 204 whole tissue samples of CRC were examined by immunhistochemistry. Clinical data was also collected.ResultsLevels of VM, ALDH1 and MVD were significantly higher, and levels of KAI1 significantly lower, in CRC tissues than in normal colorectal tissues. Levels of VM, ALDH1 and MVD were positively associated with invasion of depth, lymph node metastasis (LNM), distant metastasis and tumor-node-metastasis (TNM) stages, and negatively with patients’ overall survival (OS). Levels of KAI1 was negatively correlated with invasion of depth, LNM, distant metastasis and TNM stages, and the KAI1 positive expression subgroup had significantly longer OS than did the KAI1- subgroup. In multivariate analysis, high levels of VM, ALDH1 and KAI1, as well as TNM stages were independently correlated with lower OS in patients with CRC.ConclusionsVM, MVD and the expression of ALDH1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for CRC.