1 Acta Pharmacologica Sinica 2010 Vol: 31(9):1165-1171. DOI: 10.1038/aps.2010.94

Chromosome 1q21 amplification and oncogenes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. During human multistep hepatocarcinogenesis, genomic gain represents an important mechanism in the activation of proto-oncogenes. In many circumstances, activated oncogenes hold clinical implications both as prognostic markers and targets for cancer therapeutics. Gain of chromosome 1q copy is one of the most frequently detected alterations in HCC and 1q21 is the most frequent minimal amplifying region (MAR). A better understanding of the physiological and pathophysiological roles of target genes within 1q21 amplicon will significantly improve our knowledge in HCC pathogenesis, and may lead to a much more effective management of HCC bearing amplification of 1q21. Such knowledge has long term implications for the development of new therapeutic strategies for HCC treatment. Our research group and others, focused on the identification and characterization of 1q21 target genes such as JTB, CKS1B, and CHD1L in HCC progression. In this review, we will summarize the current scientific knowledge of known target genes within 1q21 amplicon and the precise oncogenic mechanisms of CHD1L will be discussed in detail.

Mentions
Figures
Figure 1: Amplification of different regions along chromosome 1q in 60 clinical HCC specimens. Amplification of 1q21 is most frequent chromosomal alteration in chromosome 1q in HCC. Figure 2: The role of CHD1L in Nur77-mediated pathway during hepatocarcinogenesis. In normal condition, Nur77 localizes in nucleus. In response to apoptosis stimuli, Nur77 translocates from nucleus to mitochondria where it binds to Bcl-2 and induces its conformational change, thereby leading to cytochrome c (Cyt c) release into cytoplasm and the initiation of caspase activation and apoptosis. In HCC, CHD1L, which is overexpressed caused by 1q21 amplification, are able to inhibit the nucleus-to-mitochondria translocation of Nur77, resulting in the hindrance of cytochrome c (Cyt c) release, caspase activation and apoptosis. Figure 3: During HCC progression, CHD1L is overexpressed and activates ARHGEF9 transcription via a protein-DNA interaction (). CHD1L enhances the GTP loading onto Rho GTPase protein Cdc42 (the increased level of Cdc42-GTP) () through the up-regulation of ARHGEF9 (). CHD1L/ARHGEF9-induced Cdc42 activation leads to more filopodia formation as a characteristic of actin cytoskeletal rearrangement and the concomitant EMT phenotype (). CHD1L-dependent EMT may result in a sequential process including the loss of cell-cell contact, the penetration of basement membrane (BM) and the entry of tumor cells into blood circulation (intravasation) (), finally the growth of tumor cells in the secondary sites in liver (intrahepatic metastases or microsatellite formation) or new organs (distant metastases) (). Figure 4: Healthy liver that undergoes chronic hepatitis or cirrhosis, progresses through hyperplastic and dysplastic stages. During these stages, cytogenetic alterations often occur including amplication of 1q21 which has been detected in over 50% of HCC specimens. Therefore, CHD1L is amplified and overexpression in HCC cases. By using molecular biological techniques, we delineated two molecular pathways (CHD1L)-(Nur77)-(Cyt c) and (CHD1L)-(ARHGEF9)-(Cdc42)-(EMT), which led to evasion of apoptosis, the decreased sensitivity to chemotherapy and the promotion of tissue invasion and metastasis.
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15 . . .
    • . . . In particular, gain of chromosome 1q21–23 and 8q22–24 has been associated with the early development of HCC16, 23, whereas gain of 3q has been linked to tumor recurrence and poor overall patient survival24 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
    • . . . Several minimal amplified regions (MARs) on 1q were mapped including 1q12–q2217, 25, 1q23.3–q25.327 and 1q23.1–1q4328 . . .
  18. Chang J, Kim NG, Piao Z, Park C, Park KS, Paik YK, et al. Assessment of chromosomal losses and gains in hepatocellular carcinoma. Cancer Lett 2002; 182: 193-202 , .
    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
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    • . . . As listed in Table 1, chromosomal losses are frequently detected in HCC patients at 1p (36%–37%), 4q (32%–70%), 6q (19%–37%), 8p (26%–77%), 13q (16%–55%), 16p (14%–70%), and 17p (10%–60%) while gains are often detected at 1q (46%–86%), 6p (20%–33%), 8q (31%–83%), 17q (29%–48%), and 20q (5%–37%)13, 14, 15, 16, 17, 18, 19, 20, 21, 22 . . .
    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
    • . . . In addition, Midorikawa et al. demonstrated that a regional 1q21-23 gain (74%) was significantly associated with HCC by expression imbalance map (EIM) analysis which can detect mRNA expression imbalance linked to chromosomal regions, and they also identified two candidate genes SHC1 and CKS1B within 1q21 region22 . . .
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    • . . . In particular, gain of chromosome 1q21–23 and 8q22–24 has been associated with the early development of HCC16, 23, whereas gain of 3q has been linked to tumor recurrence and poor overall patient survival24 . . .
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    • . . . In particular, gain of chromosome 1q21–23 and 8q22–24 has been associated with the early development of HCC16, 23, whereas gain of 3q has been linked to tumor recurrence and poor overall patient survival24 . . .
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    • . . . In addition, deletion of 8p has been correlated with HCC metastasis25. . . .
    • . . . Several minimal amplified regions (MARs) on 1q were mapped including 1q12–q2217, 25, 1q23.3–q25.327 and 1q23.1–1q4328 . . .
    • . . . Gain of 1q is one of the most frequently detected alterations in HCC and has been identified as an genomic event associated with early development of HCC25 . . .
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    • . . . Using comparative genomic hybridization (CGH), we and other groups, have demonstrated that copy number gain of chromosome 1q is one of the most frequently detected alterations in HCC13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and has been suggested as an early genomic alteration during HCC progression26 . . .
    • . . . In HCC, regional 1q21–q22 gains were found in 40% of advanced metastatic HCC cases26 . . .
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    • . . . Several minimal amplified regions (MARs) on 1q were mapped including 1q12–q2217, 25, 1q23.3–q25.327 and 1q23.1–1q4328 . . .
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    • . . . Several minimal amplified regions (MARs) on 1q were mapped including 1q12–q2217, 25, 1q23.3–q25.327 and 1q23.1–1q4328 . . .
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    • . . . In ovarian cancer and neuroblastoma, 1q21–q22 amplification has been suggested to be correlated with a drug-resistant phenotype31, 32 . . .
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    • . . . In the past three years, our research group showed that 1q21 was the most frequently amplified region in chromosome 1q and its amplification has been detected in 36/60 (60%) of HCC specimens33 (Figure 1) . . .
    • . . . Recently, our research group isolated a novel candidate oncogene CHD1L by using microdissected DNA from 1q21 and hybrid selection33 . . .
    • . . . We found that amplification of CHD1L at genomic level and overexpression of CHD1L at protein level were detected in 50.6% (86/170) and 52.4% (163/311) of informative HCC tissues, respectively33 (Table 2). . . .
    • . . . The sequence homology of the helicase domain (107 aa) between CHD1L and CHD1 is 59%33 . . .
    • . . . We have demonstrated that 1) CHD1L-transfected cells are able to form more colonies in soft agar and caused tumor formation in nude mice; 2) the transformation ability of CHD1L is effectively inhibited by small interference RNA (siRNA) against CHD1L; 3) CHD1L can promote the G1/S transition and inhibit apoptosis in response to cellular stress33 . . .
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    • . . . In human solid tumors, the copy number alterations are believed to contribute to the tumorigenesis by affecting the functions of cancer-related genes in the altered chromosomal regions34 . . .
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    • . . . Inagaki et al reported a novel 1q21 amplicon in HCC-derived cell lines using high-density single nucleotide polymorphism (SNP) array35 . . .
    • . . . Using fluorescence in situ hybridization (FISH) and real-time quantitative PCR, they identified three candidate targets CREB3L4, INTS3, and SNAPAP within 700-kb amplified 1q21 region and found these targets were all significantly overexpressed in tumors from HCC patients35 (Table 2) . . .
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    • . . . Wong et al found that the expression levels of JTB and SHC1 in 1q21 amplicon were significantly higher than the paired adjacent non-malignant liver tissues36 (Table 2) . . .
    • . . . The average level of JTB expression in HCC tumor cells was 1.9-fold higher than paired nontumor liver tissues36 . . .
    • . . . Wong et al reported the expression of SHC1 gene at mRNA level was significantly higher than the adjacent nontumor liver tissues36 . . .
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    • . . . Malignant hepatocytes result from step-by-step changes that accumulate in mature hepatocytes or can be derived from stem cells37 . . .
    • . . . At this advanced stage, angiogenesis, tissue invasion, and metastases occur in up to 25% of cases37 . . .
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    • . . . The most widely accepted hypothesis describes a sequential process in which this stepwise transformation begins in the liver tissue that undergoing chronic hepatitis or cirrhosis caused by external stimuli (HBV or HCV infection, alcohol or metabolic diseases), progresses through a series of hyperplastic and dysplastic stages (low- and high-grade dysplastic) stages, and progresses further to become more malignant, making metastases possible38, 39 . . .
  39. Theise ND, Park YN, Kojiro M. Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis 2002; 6: 497-512 , .
    • . . . The most widely accepted hypothesis describes a sequential process in which this stepwise transformation begins in the liver tissue that undergoing chronic hepatitis or cirrhosis caused by external stimuli (HBV or HCV infection, alcohol or metabolic diseases), progresses through a series of hyperplastic and dysplastic stages (low- and high-grade dysplastic) stages, and progresses further to become more malignant, making metastases possible38, 39 . . .
  40. Qi H, Fillion C, Labrie Y, Grenier J, Fournier A, Berger L, et al. AIbZIP, a novel bZIP gene located on chromosome 1q21.3 that is highly expressed in prostate tumors and of which the expression is up-regulated by androgens in LNCaP human prostate cancer cells. Cancer Res 2002; 62: 721-33 , .
    • . . . CREB3L4 (cyclic AMP responsive element binding protein3-like 4), belongs to the CREB/ATF family of transcriptional factor40 . . .
    • . . . Immunostaining analysis showed that the expression of CREB3L4 at protein level were higher in prostate cancer than the adjacent noncancerous tissues40, whereas the functional role of CREB3L4 in HCC remains to be revealed . . .
  41. Pan JS, Cai JY, Xie CX, Zhou F, Zhang ZP, Dong J, et al. Interacting with HBsAg compromises resistance of jumping translocation breakpoint protein to ultraviolet radiation-induced apoptosis in 293FT cells. Cancer Lett 2009; 285: 151-6 , .
    • . . . JTB (Jumping Translocation Breakpoint) is a transmembrane protein which suffers an unbalanced translocation in various types of cancers41 . . .
    • . . . To elucidate the role of JTB during hepatocarcinogenesis, Pan et al found that JTB could interact with HBs (Hepatitis B surface) and overexpression of JTB inhibited ultraviolet radiation-induced apoptosis which was compromised by co-overexpression of HBs41 . . .
  42. Kanome T, Itoh N, Ishikawa F, Mori K, Kim-Kaneyama JR, Nose K, et al. Characterization of Jumping translocation breakpoint (JTB) gene product isolated as a TGF-beta1-inducible clone involved in regulation of mitochondrial function, cell growth and cell death. Oncogene 2007; 26: 5991-6001 , .
    • . . . Wild-type JTB confers resistance to apoptosis induced by TGF-β142 . . .
  43. Huebner K, Kastury K, Druck T, Salcini AE, Lanfrancone L, Pelicci G, et al. Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2). Genomics 1994; 22: 281-7 , .
    • . . . Huebner et al assigned the SHC1 gene to 1q2143 . . .
    • . . . Shc is involved in signal transduction from receptor tyrosine kinases to downstream signal recipients such as Ras43, 44 . . .
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    • . . . Shc is involved in signal transduction from receptor tyrosine kinases to downstream signal recipients such as Ras43, 44 . . .
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    • . . . Importantly, there is now a transgenic mouse model with ubiquitous CHD1L expression55 . . .
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    • . . . Chen et al revealed that the anti-apoptotic ability of CHD1L was found to be linked to its interaction with Nur77, a critical member of a p53-independent apoptotic pathway56 . . .
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    • . . . CHD1L was also found to be endowed with DNA binding activity57 . . .
    • . . . Both in vitro and in vivo functional studies found that CHD1L could increase cell motility, induce filopodia formation and the epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation, all contributing to tumor cell invasion and metastasis57 (Figure 3) . . .
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