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Nerve growth factor-induced clone B (NGFI-B), Nur-related factor 1, and neuron-derived orphan receptor-1 have structural features of ligand-activated transcriptional regulators and constitute the NGFI-B subfamily within the nuclear receptor superfamily. The NGFI-B subfamily is highly expressed in neuroendocrine organs and regulates the pro-opiomelanocortin (POMC) gene. Small-cell lung cancer (SCLC) is considered to be a neuroendocrine tumor that produces large numbers of polypeptide hormones. In this study we measured the NGFI-B subfamily and POMC messenger RNA (mRNA) levels in various lung-cancer cell lines by means of the quantitative reverse transcription-polymerase chain reaction, and evaluated the correlations between expression of these genes and polypeptide hormone productions. We also examined the effect of antisense oligonucleotide to NGFI-B mRNA on the expression of POMC mRNA. The NGFI-B subfamily and POMC mRNAs were highly expressed in SCLC cell lines. In addition, there were strong correlations between the NGFI-B, POMC genes, and the adrenocorticotropin hormone (ACTH) level. Further, the antisense oligonucleotide significantly suppressed POMC gene expression. We conclude that the NGFI-B subfamily was a significant molecule in SCLC and that the NGFI-B was a positive transcriptional factor for ACTH production.
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Nuclear receptors comprise a superfamily of structurally related transcription factors that control a variety of developmental, physiologic, and behavioral processes (1). The family includes receptors for lipophilic hormones and vitamins as well as a majority of orphan members whose physiologic functions are poorly understood (4). Nerve growth factor-induced clone B (NGFI-B) (also called nur77, TR3, N10, and NAK1) is an orphan receptor member of the superfamily (5). The protein exhibits a close structural relationship to the orphan receptors Nur-related factor 1 (Nurr1) (also called RNR-1 and NOT) (10) and neuron-derived orphan receptor-1 (NOR-1) (also called MINOR and TEC) (13). All three proteins are members of a nuclear receptor subgroup that is called the NGFI-B subfamily. This subfamily is said to be an important factor in a variety of fields, such as differentiation and proliferation of neurocytes, T-cell receptor-induced apoptosis, retinoic acid signal transduction, and carcinogenesis (16). A tissue distribution study of the NGFI-B subfamily messenger RNA (mRNA) revealed that its expression was markedly high in the pituitary gland and the adrenal glands. Nurr1 and NOR-1 gene expression was uniformly low except in the pituitary gland, and lower than that of the NGFI-B gene in all adult tissues examined (10, 18, 26). Therefore, the NGFI-B subfamily gene is highly expressed in the neuroendocrine organs.
Several lines of evidence indicate that the members of the NGFI-B subfamily may have played an important role in the organization of neuroendocrine regulation of the hypothalamic/pituitary/adrenal axis. Corticotropin-releasing hormone (CRH) released from the hypothalamus increases both the secretion of adrenocorticotropic hormone (ACTH) and the transcription of the pro-opiomelanocortin (POMC) gene in the pituitary gland (27). In addition, current evidence suggests that the transcriptional effect of CRH on POMC expression is mediated through activation of NGFI-B (28). It has also been reported that the POMC transcriptional activity markedly decreases if the NGFI-B response element (NBRE) within the POMC promoter is artificially mutated in the mouse pituitary tumor cell line (AtT-20) (29). In contrast, POMC activity is unchanged when mutations or deletions do not occur within the NBRE (29). Moreover, it has been reported that glucocorticoids and their receptors antagonize signals mediated through the CRH/NGFI-B signaling pathway and that NGFI-B antagonizes negative feedback of ACTH synthesis and secretion by glucocorticoid (29, 30).
Small-cell lung cancer (SCLC) is considered to be a neuroendocrine tumor. It produces several polypeptide hormones: ACTH, pro-gastrin-releasing peptide (pro-GRP), antidiuretic hormone (ADH), and calcitonin. We hypothesized that the NGFI-B subfamily is a very important regulator of the POMC expression in SCLC cells. So we also assumed that the NGFI-B subfamily is highly expressed in SCLC cells and that it participates in hormone production and secretion. However, the effects of the NGFI-B subfamily on the neuroendocrine functions of SCLC have not been evaluated. In this study we used a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method to measure expression of the NGFI-B subfamily mRNA as well as POMC mRNA in various lung-cancer cell lines. In addition, correlations between the level of NGFI-B subfamily mRNA expression and the levels of several polypeptide hormones were examined. Further, we also examined the effect of antisense oligonucleotide to NGFI-B mRNA on the expression of POMC mRNA in a SCLC cell line.
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Lung-Cancer Cell Lines
Nine SCLC cell lines and seven non-SCLC (NSCLC) cell lines (including four adenocarcinoma [Ad] and three squamous-cell carcinoma [Sq] cell lines) were prepared for this study. SCLC cell lines M-319, MN-321, MN-321R, MN-1112, MT-428, TK-130R, and TO-1019 were established in our laboratory (31). The other two SCLC cell lines, Lu-139 and Lu-165, were obtained from the Riken Cell Bank (Ibaragi, Japan). NSCLC cell lines A-549 (Ad), Lc-1/Sq, and RERF-LC-AI (Sq) were obtained from the Riken Cell Bank; and PC-3 (Ad), PC-9 (Ad), RERF-LC-OK (Ad), and EBC-1 (Sq) were obtained from the Japan Cancer Research Resources Bank (Tokyo, Japan). All cell lines were cultured in a growth medium consisting of RPMI-1640 supplemented with 10% fetal calf serum. All incubations were carried out at 37°C in 5% CO2 atmosphere. All cell lines used in this study had similar doubling times. Total RNA from various lung-cancer cell lines was extracted with acid guanidinium thiocyanate-phenol/ chloroform.
Quantitative RT-PCR of the NGFI-B Subfamily
The amounts of NGFI-B, Nurr1, and NOR-1 mRNA were
measured by the quantitative RT-PCR technique as described previously (17, 18, 24, 32). We used in vitro-synthesized RNAs as internal standards that had 56-base pair
(bp) deletion, 42-bp deletion, and 72-bp insertion within
authentic sequences of the NGFI-B subfamily, respectively (13). Complementary DNA (cDNA) was generated
by RT of 1 µg RNA in the presence of the internal standard RNA. SUPERSCRIPT II RNase H
Reverse Transcriptase (GIBCO BRL, Gaithersburg, MD) and specific RT primers (17, 18, 24, 32) were used for RT for NGFI-B, Nurr1, and NOR-1. The expected PCR products of NGFI-B, Nurr1, and NOR-1 were 358, 352, and 418 bp long, respectively. The cDNA of the NGFI-B subfamily mRNA
and the internal standard RNA were amplified by PCR
with primers as described previously (13) under the following conditions: 1 min at 95°C, 2 min at 66°C, and 3 min
at 72°C for 25, 33, and 33 cycles for NGFI-B, Nurr1, and
NOR-1, respectively, with the final extension at 72°C for
10 min. The PCR products were separated in a 10% polyacrylamide gel in Tris Borate/ethylenediaminetetraacetic
acid (TBE) buffer, and their radioactivity was measured
with an imaging analyzer (The National Cancer Center
Research Institute, Tokyo, Japan). The validity of these
RT-PCRs were evaluated previously (17, 18, 24, 32).
Comparison of values between SCLC and NSCLC was analyzed with the Mann-Whitney U test.
Quantitative RT-PCR of the POMC
A simple quantitative RT-PCR method was performed to
quantitate the expression of mRNA for POMC. A commercial kit (Competitive RNA Transcription Kit, Code No.
6125; TaKaRa, Tokyo, Japan) was used to generate a nonhomologous internal standard as a template for recombinant RNA. This internal standard contained the same primer
pair as the target mRNA but yielded a PCR product of a different size (280 bp). Thus, the two PCR products (492 and 280 bp) could easily be separated by gel electrophoresis after amplification. The amount of 1 µg of the total
RNA was reverse transcribed into cDNA. For RT, we
used SUPERSCRIPT II RNase H Reverse Transcriptase
and oligo dT as RT primer. The cDNA of POMC mRNA
and the internal standard RNA were amplified by PCR with primers: sense primer 5'-AGAAGCGCGAGGAC-GTCTCA-3' and antisense primer 5'-CCTTCTTGTAGGCGTTCTTG-3'; under the following conditions: 70 s at
96°C, 2 min at 61°C, and 3 min at 72°C for 40 cycles, with
the final extension at 72°C for 10 min. The PCR products were separated in a 10% polyacrylamide gel in TBE buffer, and their radioactivity was measured with an imaging
analyzer. Comparison of values between SCLC and
NSCLC was analyzed with the Mann-Whitney U test.
Hormone Assay
ACTH, pro-GRP, and ADH were assayed by immunoradiometric assay, enzyme immunoassay, and radio immunoassay, respectively, at the Otuka Assay Laboratories (Tokushima, Japan). All three hormones were measured using the supernatant of culture medium after the cells were cultured for 7 d. Approximately 1 × 107 cells in 10-cm plates were used.
Treatment of Antisense, Sense, and Random Oligonucleotide to the SCLC Cell Line Lu-139
Phosphorothioate antisense oligonucleotide was designed to hybridize to the initiation site on NGFI-B mRNA. The oligonucleotide was a 21-mer (5'-AAGGCATGGCTTCAGCCGAGT-3') that was complementary to nucleotides 88 to 108 (nucleotide 103 begins with a AUG codon) of NGFI-B mRNA. Treatment of sense oligonucleotide (5'-ACTCGGCTGAAGCCATGCCTT-3') or random oligonucleotide (5'-GACATGAGGACTATAGCTACC-3') was also performed. Each oligonucleotide (1 µM) was added to the culture supernatant (Lu-139 cells were 70% confluent) and total RNA was extracted after 48 h. Quantitative RT- PCR of POMC was performed as described previously. Student's t test was used for comparisons.
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Quantitative RT-PCR for the NGFI-B Subfamily mRNAs
In the presence of 0.5 attomoles of competitor for the NGFI-B, it was possible to quantitate the expression of NGFI-B mRNA in SCLC and NSCLC (Figures 1a and 1b). The level of expression of NGFI-B mRNA in SCLC cell lines (242.2 ± 42.4, range 145 to 515) was significantly high compared with that of NSCLC cell lines (52.1 ± 7.47, range 25.0 to 85.0, P < 0.001; Figure 1c).
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In the presence of 0.0125 attomoles of competitor for the Nurr1 or 0.05 attomoles of competitor for the NOR-1 internal standard RNA, it was possible to quantitate the expression of Nurr1 mRNA and NOR-1 mRNA in SCLC and NSCLC (data not shown). The level of expression of Nurr1 mRNA in SCLC cell lines (102.9 ± 39.5, range 15.5 to 386) was significantly high compared with that of NSCLC cell lines (11.79 ± 2.63, range 5.38 to 24.8, P < 0.005; Figure 2a). The level of expression of NOR-1 mRNA in SCLC cell lines (35.9 ± 13.3, range 4.50 to 105) was significantly high compared with that of NSCLC cell lines (4.79 + 1.54, range 1.0 to 10.5, P < 0.01; Figure 2b). In SCLC cell lines, there were no significant differences between variant and classic subtypes in the expression of the NGFI-B subfamily.
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Quantitative RT-PCR for POMC mRNA
RT-PCR using 1 µg of total RNA with a dilution series of recombinant RNA was performed. To examine the ability of the competitive RT-PCR to detect accurately a relatively small change in the level of POMC mRNA, four dilutions of total RNA were prepared and used for the competitive RT-PCR. At the point where the sample cDNA and competitor cDNA products were in equivalence, the starting concentration of sample RNA was equal to the known starting concentration of the competing recombinant RNA. With competitive RT-PCR, a linear relationship between concentrations of recombinant RNA and ratios of input RNA samples divided by recombinant RNA was obtained, suggesting that this RT-PCR could be used to quantify POMC mRNA. The calculated amount of POMC mRNA was significantly high in SCLC (168.6 ± 76.6, range 1.7 to 740.8) compared with that in NSCLC (4.31 ± 4.0, range 0.027 to 28.3, P < 0.005; Figure 3). In SCLC cell lines, there were no significant differences in the expression of POMC between variant and classic subtypes.
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Hormone Levels and Their Correlation with the Expression of NGFI-B Subfamily and POMC Gene
Levels of ACTH, ADH, and pro-GRP in culture supernatants of SCLC cell lines as well as NSCLC cell lines are listed in Table 1. Levels of ACTH correlated significantly with the expression of NGFI-B gene (coefficient of correlation: r = 0.864, P < 0.0001; Figure 4), but was unrelated to the Nurr1 or NOR-1 genes (r = 0.227, P = 0.4052; and r = 0.145, P = 0.5994, respectively). Expression of the POMC gene correlated with expression of the NGFI-B gene (coefficient of correlation: r = 0.868, P < 0.0001; Figure 5), but were unrelated to expression of the Nurr1 or NOR-1 genes (r = 0.221, P = 0.418; and r = 0.024, P = 0.9306, respectively). There were no significant correlations between pro-GRP or ADH and expression of NGFI-B, Nurr1, or NOR-1 genes.
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Effect of Antisense Oligonucleotide to NGFI-B mRNA on the Expression of POMC mRNA in the Lu-139 Cell Line
There were no growth or morphologic changes in this experiment. The expression of POMC mRNA was significantly decreased by the addition of antisense oligonucleotide to NGFI-B mRNA in the Lu-139 cell line (10.9 ± 0.4) compared with the control (51.2 ± 12.7, P < 0.05). In contrast, the addition of sense oligonucleotide or random oligonucleotide did not suppress the expression of the POMC mRNA (47.6 ± 3.5 and 52.8 ± 15.2, respectively; not significant) compared with the control (Figure 6). The same results were seen in the MN-321R cell line (data not shown).
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We have demonstrated here that the transcripts of the NGFI-B subfamily and POMC are present in all lung-cancer cell lines examined, and that the NGFI-B subfamily gene was expressed much higher in SCLC cell lines than in NSCLC cell lines. In addition, there was correlation between the NGFI-B and POMC gene expressions, as well as between the NGFI-B gene expression and ACTH secretion. Furthermore, antisense of NGFI-B suppressed the expression of POMC mRNA.
The NGFI-B subfamily that contains NGFI-B, Nurr1, and NOR-1 is a closely related orphan receptor and all members are immediate-early protein-inducible in diverse cultured cells (5, 12, 13, 33). They can all bind to the NBRE, and all display translational activity in the absence of an exogenously supplied ligand under all culture conditions examined (11, 14, 36, 37). The tissue distribution patterns of their mRNAs are also similar. Although NGFI-B, Nurr1, and NOR-1 genes are highly expressed in the pituitary and adrenal glands, the NGFI-B gene expression was much higher than that of Nurr1 and NOR-1 in all tissue examined (10, 18, 26), suggesting that NGFI-B plays the most important role in the coordination of neuroendocrine functions.
Recently, experiments using reporter genes that are inserted into the POMC promoter proved that the mutation of the NBRE markedly decreases transcriptional activities of POMC; however, other sites of mutations or deletions do not change activities (29). Therefore, although there are several response elements within the POMC promoter, the NGFI-B subfamily is presently considered to be a strong factor in POMC transcription.
SCLC is known to be a neuroendocrine tumor and to produce several polypeptide hormones: ACTH, ADH, pro-GRP, and calcitonin, for example. Recently, it has been reported that new transcriptional factors are essential for neuroendocrine differentiation in the lung (38). However, SCLC secretes not only ACTH but also precursor forms of ACTH, POMC, and pro-ACTH. POMC with a molecular weight of approximate 31 kD is cleaved to yield an intermediate ACTH-containing peptide, designated pro-ACTH, and is produced primarily by the pituitary but can be detected in the lung, thyroid, brain, gastrointestinal tract, reproductive tract, and leukocytes (39). POMC is also found in tumors of nonpituitary origin, particularly SCLC, which is well recognized for its ability to produce ACTH-related peptides (40).
It has been reported that the predominance of ACTH precursors and the absence of processing product (ACTH) are observed in human SCLC cell lines that produce ACTH-related peptides (41), and that POMC transcripts of a similar size are present in a number of ectopic ACTH-producing tumors (42).
It is reported that NGFI-B induced by CRH binds to the NBRE within the POMC gene promoter in a sequence-specific manner, and it antagonizes negative feedback of ACTH synthesis and secretion by glucocorticoid (30). Therefore, the NGFI-B subfamily is thought to be very important with regard to POMC transcription. In our study we first demonstrated that the transcripts of the NGFI-B subfamily and POMC were present in all lung-cancer cell lines examined and that expression of the NGFI-B subfamily genes was much higher in SCLC cell lines than in NSCLC cell lines. In addition, there was a correlation between the NGFI-B and POMC gene expression, as well as between the NGFI-B gene expression and ACTH secretion. Furthermore, antisense of NGFI-B significantly suppressed the expression of POMC. Therefore, although quantitative RT-PCR analysis has potential limitations, our study demonstrates that NGFI-B regulates the expression of POMC and ACTH in SCLC and that it works as a positive transcriptional factor, in accordance with a previous study (30).
In the present study there was a correlation between the POMC and the NGFI-B gene expression, but no correlation was seen between the POMC and the Nurr1 or NOR-1 gene expression. This evidence suggests that NGFI-B dominantly regulated the POMC gene in lung-cancer cells because its expression was much higher than other NGFI-B subfamilies, Nurr1, or NOR-1. However, the possibility that Nurr1 and NOR-1 played an important role cannot be excluded because their expression is higher in SCLC cell lines compared with that in NSCLC. In addition, there were no correlations between the expression of the NGFI-B subfamily and the secretion of pro-GRP and ADH. These results may suggest the absence of NBRE within the promoters of pro-GRP or ADH.
In clinical aspects, it is known that there are numerous hormone-producing tumors. However, the mechanism of hormone production and secretion is unclear and effective therapies for these tumors are unavailable except for complete surgical removal. We demonstrate here that POMC gene expression is decreased by the addition of antisense oligonucleotide. Therefore, it is suggested that NGFI-B participates in these tumors significantly, and it may be possible to control their neuroendocrine manifestations by using receptor antagonists.
It has been suggested that the mechanism of POMC gene expression in SCLC cells is different from that in pituitary cells (47, 48). In addition, it has also been reported that ACTH secretion by tumors of nonpituitary origin is characteristically resistant to negative feedback regulation by glucocorticoids (48). Therefore, differences in regulation of POMC expression by NGFI-B between SCLC cells and pituitary cells should be evaluated in future studies.
In conclusion, we found that the NGFI-B subfamily is a significant molecule in SCLC and NGFI-B is a positive transcriptional factor for the production of ACTH.
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Address correspondence to: Shuji Bandoh, M.D., Ph.D., First Department of Internal Medicine, Kagawa Medical University, 1750-1, Ikenobe, Oaza, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
(Received in original form October 2, 1998 and in revised form January 22, 1999).
Abbreviations: adrenocorticotropic hormone, ACTH; adenocarcinoma, Ad; antidiuretic hormone, ADH; base pairs(s), bp; complementary DNA; cDNA; corticotropin-releasing hormone, CRH; messenger RNA, mRNA; NGFI-B response element, NBRE; nerve growth factor-induced clone B, NGFI-B; neuron-derived orphan receptor, NOR-1; non-SCLC, NSCLC; Nur-related factor-1, Nurr1; pro-opiomelanocortin, POMC; pro-gastrin- releasing peptide, pro-GRP; reverse transcription-polymerase chain reaction, RT-PCR; small-cell lung cancer, SCLC; standard error, SE; squamous-cell carcinoma, Sq.Acknowledgments: The authors thank Drs. Toshihiko Tsukada and Ken Yamaguchi (National Cancer Center Research Institute, Tokyo, Japan) for their excellent advice.
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