Kai1, A New Metastasis Suppressor Gene, Is Reduced in Metastatic Hepatocellular Carcinoma

Abstract

Down-regulation of KAI1 expression has been shown to be associated with formation of metastases or disease progression in prostate and pancreatic cancer. In the present study we analyzed the expression pattern of KAI1 in metastatic and nonmetastatic hepatocellular carcinomas (HCCs) in comparison with normal livers to evaluate whether alteration of KAI1 also facilitates the metastatic ability in this malignancy. Thirty-nine primary HCCs and 10 normal liver tissue samples were studied for KAI1 messenger RNA (mRNA) expression with use of Northern blot analysis and in situ hybridization. By Northern blot analysis, moderate to strong KAI1 mRNA expression was present in normal liver samples. In contrast, KAI1 mRNA expression in tissue samples of primary HCCs was markedly decreased compared with normal controls. The normal/ tumor ratio of KAI1 mRNA expression was 2.6:1 (P F .01). Primary HCCs that gave rise to metastasis showed significantly lower KAI1 mRNA levels than nonmetastasized HCCs (P F .05). As seen by in situ hybridization, moderate to strong cytoplasmic KAI1 mRNA staining was present in almost all normal hepatocytes. Bile ducts, blood vessels, and connective tissue showed no or only faint KAI1 mRNA expression in the normal liver samples. In nonmetastatic HCCs, the cancer cells exhibited in situ hybridization signals that were similar to the normal controls. In contrast, most of the primary HCC cells in samples with metastases showed only faint or moderate KAI1 mRNA expression predominantly in the perinuclear regions. When KAI1 mRNA expression of primary hepatocellular cancer cells was compared with metastasized cancer cells in lymph nodes, with intrahepatic satellite metastasis, or with peritoneal metastasis in the same patients, significantly lower (P F .01) KAI1 mRNA levels were present in the metastasized HCC cells. Reduced KAI1 mRNA in HCC cells seems to influence their metastatic ability and thereby enhances the malignant potential of HCC. (HEPATOLOGY 1998;28:1481-1488.)HCC is a challenging disease because of limitations in surgical treatment and its unresponsiveness to adjuvant chemotherapy, radiotherapy, and/or antihormonal treatment. Therefore, the incidence and cancer-related mortality are almost identical and reflect the dismal clinical course of the disease. The best therapeutic option to cure patients with HCC is surgical resection. However, despite successful resection, patients with HCC have a high rate of tumor recurrence and metastasis, resulting in short survival time. 1,2 Although the high incidence of recurrence can partly be attributed to the often-associated cirrhosis in the remaining liver, certain characteristics of the cancer cells may be related to tumor recurrence, even in small carcinomas. Primary HCC and tumor recurrences in the remnant liver are often associated with extrahepatic and intrahepatic metastases occurring via the portal and lymphatic systems. 3,4 Thus, the presence of intrahepatic metastases and tumor thrombosis of the portal vein and its branches are considered to be...

Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

“…However, recently, RUVBL2 was also found to be required for the repressing effect of ␤-catenin on the transcription of the antimetastatic gene KAI-1, 36 which is frequently down-regulated in HCC. 37 In our study of a large number of HCC samples, there were, however, no correlations between the levels of expression of RUVBL2 and ␤-catenin target genes. It is thus likely that additional mechanisms, independent of ␤-catenin, may also explain the oncogenic properties of RUVBL2.…”

Genetic mechanisms of hepatocarcinogenesis

“…Inactivation of the gene that encodes the integral membrane protein, KAI-1, which appears to function in cell-cell and cell-extracellular matrix interactions, is strongly down-regulated in metastatic HCC nodules (Guo et al, 1998) as well as other metastatic tumor types (Dong et al, 1995), suggesting that KAI-1 is a tumor suppressor whose integrity prevents metastasis. Increased expression of other oncogenes has also been documented in large tumors.…”

Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma

“…On the other hand, oncogenes and certain cell cycle controllers, such as c-myc (Wu et al, 1996), c-Jun, c-fos (Twu et al, 1993), c-met (Boix et al, 1994;Grigioni et al, 1995), cets-1 (Ozaki et al, 2000), cyclin D1 (Peng et al, 1998;Deane et al, 2001;Joo et al, 2001), cyclin E (Peng et al, 1998), and gankyrin (Higashitsuji et al, 2000), were overexpressed or re-expressed in the later stage of hepatocellular carcinogenesis. Finally, some genes involved in cell-cell or cell-extracellular matrix interactions, such as MMPs (Arii et al, 1996), integrin a6b1 (Begum et al, 1995), syndecan-1, nm23 (Fujimoto et al, 1998), and KAIL (Guo et al, 1998), were reported to play important roles in HCC progression due to correlation with invasive and metastatic potentials.…”