WO2013191242A1 - Procédé de test et moyens de traitement pour le cancer du poumon à petites cellules ayant un faible pronostic - Google Patents

Procédé de test et moyens de traitement pour le cancer du poumon à petites cellules ayant un faible pronostic Download PDF

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WO2013191242A1
WO2013191242A1 PCT/JP2013/066947 JP2013066947W WO2013191242A1 WO 2013191242 A1 WO2013191242 A1 WO 2013191242A1 JP 2013066947 W JP2013066947 W JP 2013066947W WO 2013191242 A1 WO2013191242 A1 WO 2013191242A1
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lung cancer
small cell
cell lung
hotair
poor prognosis
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石川　雄一
宏 小野
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公益財団法人がん研究会
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention relates to a test method, biomarker, and treatment means that can detect small cell lung cancer with poor prognosis among small cell lung cancer.
  • Lung cancer is one of the intractable cancers, and both morbidity and mortality begin to increase in the late 40s, and become higher as the elderly get older. There is no significant difference in the number of morbidity and death, which is related to the low survival rate of those with lung cancer, and there is a need for the development of useful laboratory diagnostics and treatments.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • tissue types such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and adenosquamous cell carcinoma.
  • SCLC is classified as a neuroendocrine cancer tissue type, accounts for about 15 to 20% of lung cancer, and generally shows a unique aspect such as being easier to metastasize and increase than NSCLC.
  • chemotherapy is mainly used, and it is usually difficult to operate, so it is difficult to obtain fresh materials, and research tends to be delayed, so biomarkers that lead to SCLC testing and treatment The search for is also not progressing.
  • HOTAIR RNA called HOTAIR (hereinafter simply referred to as “HOTAIR”) transcribed antisense from the HOXC cluster, which is one of the HOX genes, is long intergenic non- It is a long non-coding RNA that does not encode a protein called coding RNA (lincRNA) and is a relatively recent cancer-related gene.
  • This HOX gene group is a group of genes that make the segment of animals, and contributes to the creation of the segment during the fetal period, but is also involved in the development and progression of cancer. HOTAIR is also thought to regulate gene expression in the HOXD cluster.
  • HOTAIR High expression of HOTAIR is confirmed in primary breast cancer tissues and metastatic breast cancer tissues, and high expression of HOTAIR in primary breast cancer tissues is considered as a strong predictor of metastasis and death (Non-patent Document 1, Patent Document 1). ).
  • Patent Document 1 Patent Document 1
  • PRC Polycomb repressive complex
  • Cancers differ in biomarkers such as genes and proteins expressed by organ characteristics and phenotypes (phenotypes) and drug sensitivities, so examination methods and treatment methods need to be examined for each cancer type.
  • Breast cancer histology is mainly adenocarcinoma (invasive)
  • colon cancer is mainly epithelial and adenocarcinoma
  • liver cancer is mainly epithelial cancer, and is different from SCLC histology
  • Small cell lung cancer includes cancer with poor prognosis and cancer with good prognosis (see, for example, Example 1 and Table 1). It has been pointed out that small cell lung cancer with a poor prognosis may have already metastasized or disseminated at the time of discovery. The treatment is difficult, and therefore, early detection and establishment of a treatment method are required. Therefore, an object of the present invention is to provide a test method and a biomarker thereof that can detect small cell lung cancer with poor prognosis among small cell lung cancer. Furthermore, an object of the present invention is to provide a therapeutic agent for small cell lung cancer with a poor prognosis. Furthermore, an object of the present invention is to provide a method for screening a drug for treating small cell lung cancer with a poor prognosis.
  • the present inventors have found that HOTAIR, which is a lincRNA, is highly expressed in small cell lung cancer with a poor prognosis. Furthermore, the present inventors have found an siRNA capable of suppressing the growth of small cell lung cancer that highly expresses HOTAIR. That is, the present invention relates to a diagnostic method for determining whether small cell lung cancer (SCLC) is a small cell lung cancer with a poor prognosis, and in a small cell lung cancer (SCLC) as a specimen. It is a test method that comprises measuring the expression level of HOTAIR, which is a lincRNA, and that the higher the expression level of HOTAIR, the poorer the prognosis.
  • SCLC small cell lung cancer
  • the present invention is a biomarker for diagnosing small cell lung cancer used for determining whether small cell lung cancer (SCLC) is a small cell lung cancer with a poor prognosis, and is a lincRNA. It is a biomarker for diagnosis and diagnosis of small prognosis of small cell lung cancer, which is composed of HOTAIR and has a poorer prognosis as the expression level of HOTAIR, which is a lincRNA, is higher. Further, the present invention is a kit for use in quantifying the biomarker for testing and diagnosis of poor prognosis of small cell lung cancer so that the cDNA (SEQ ID NO: 1) of HOTAIR, which is a lincRNA, can be quantified. A kit comprising a primer to be amplified and a polymerase and / or a probe to be paired with the cDNA.
  • the present invention provides an oligoribo corresponding to a base sequence of 30 bases or less of the base sequence of SEQ ID NO: 1 comprising the base sequence of positions 801 to 819 of the base sequence (SEQ ID NO: 1) of HOTAIR, which is a lincRNA.
  • An agent for inhibiting the growth of small cell lung cancer with a poor prognosis which comprises, as an active ingredient, a double-stranded RNA comprising a nucleotide and its complementary oligoribonucleotide.
  • the present invention relates to an oligo corresponding to a base sequence of 30 bases or less of the base sequence of SEQ ID NO: 1, comprising the base sequence of 801 to 819 of the base sequence (SEQ ID NO: 1) of cDNA for HOTAIR, which is a lincRNA.
  • a kit for inhibiting the growth of small cell lung cancer with a poor prognosis comprising a double-stranded RNA comprising ribonucleotide and its complementary oligoribonucleotide.
  • the present invention relates to an agent for inhibiting the growth of small cell lung cancer with poor prognosis, comprising screening a candidate drug for inhibiting or suppressing the expression of HOTAIR, which is a lincRNA, using human cultured small cell lung cancer cells. Screening method.
  • SCLC tissue (cancer) on the left side of the figure shows the appearance of sheet-like growth of small tumor cells that are almost naked nucleus and the nucleolus is unclear.
  • Normal tissue on the right side of the figure has alveolar structure. It shows a clear aspect. Cut along the boundary indicated by the dotted line.
  • the vertical axis in the figure indicates the expression level of HOTAIR for ACTB.
  • ACTB indicates ⁇ -actin.
  • “high-HOTAIR” indicates a high HOTAIR expression group having a HOTAIR / ACTB ratio of 1.368 or more
  • “low-HOTAIR” indicates a low HOTAIR expression group having a HOTAIR / ACTB ratio of less than 1.368.
  • SCLC small cell lung cancer
  • (B) Decrease in the expression level of HOTAIR due to RNA interference (# 1 to # 3 siHOTAIR) in the SBC-3 cell line.
  • shaft shows the expression level of HOTAIR with respect to GAPDH.
  • SiGFP is a negative control.
  • One embodiment of the present invention is a test method for determining small cell lung cancer (SCLC) with a poor prognosis based on the expression level of HOTAIR.
  • SCLC small cell lung cancer
  • “poor prognosis” means that the recurrence rate is high after SCLC surgery and postoperative chemotherapy. Death is often caused by poor prognosis of SCLC.
  • SCLC components are first collected from SCLC surgical specimens.
  • rapid diagnosis and subsequent pathological diagnosis it is necessary to confirm that the collected specimen is a small cell lung cancer.
  • the quick diagnosis is performed as follows, for example.
  • SCLC components are identified visually by slicing a frozen specimen with a cryostat and performing hematoxylin-eosin staining. SCLC is small compared to normal cells, is almost like a naked nucleus, has an obscure nucleolus, and exhibits sheet-like proliferation, so it can be roughly identified visually.
  • the pathological diagnosis is performed as follows, for example.
  • the surgical specimen is fixed in formalin for several days, and then the sample is cut out.
  • the lung is sliced at a thickness of approximately 5 mm, similar to a CT scan image, to obtain a sample. It is preferable to further divide into block sizes centering on the tumor area on each surface and the surrounding related area.
  • a specimen prepared in this manner is sliced into a paraffin-embedded specimen to prepare a preparation.
  • immunostaining using an antibody of a neuroendocrine marker for example, Chromogranin A, Synaptophysin, NCAM / CD56
  • a neuroendocrine marker for example, Chromogranin A, Synaptophysin, NCAM / CD56
  • the specimen determined to be SCLC as described above may be stored, for example, as follows until the HOTAIR expression level is examined.
  • a portion of the surgical specimen that was cut off at the time of rapid diagnosis is divided into several 3 mm square tissue sections on a serum tube that has been given the specimen number on ice for research purposes. Then, it is put into liquid nitrogen, frozen, and stored in a -80 ° C freezer.
  • the stored specimen is prepared as follows. Take the serum tube of the preserved specimen from the -80 ° C freezer, take out one piece of tissue in the tube with a sterilizing cloth, place it in a new serum tube with the same number, and immediately put it into liquid nitrogen.
  • the test method of the present invention comprises measuring the expression level of HOTAIR, which is a lincRNA, in a specimen of small cell lung cancer (SCLC), and the higher the expression level of HOTAIR, the poorer the prognosis. .
  • the poor prognosis small cell lung cancer diagnostic marker used in the present invention consists of HOTAIR, which is a lincRNA.
  • HOTAIR cDNA consists of the base sequence represented by SEQ ID NO: 1 (NCBI Accession No .: NR_003716.2).
  • the expression level of HOTAIR is preferably expressed as a relative amount with respect to the expression level of the internal standard gene.
  • internal standard genes include glyceraldehyde-3-phosphate dehydrogenase (also referred to as “GAPDH”), ⁇ -actin (also referred to as “ACTB”), IPO8, etc.
  • GAPDH Genbank Accession No .: NM_002046.3
  • GAPDH Genbank Accession No .: NM_002046.3
  • ⁇ -actin gene As an internal standard, and when examining HOTAIR in cancer cells, it is preferable to use GAPDH gene as an internal standard (BMC Mol Biol. 2008). 9: 103).
  • the test method of the present invention further includes measuring the expression level of a gene serving as an internal standard in small cell lung cancer (SCLC), and is a lincRNA HOTAIR that is an expression level of the gene serving as an internal standard.
  • SCLC small cell lung cancer
  • the small prognosis marker for small cell lung cancer of the present invention further comprises an mRNA expressed from a gene serving as an internal standard, and the expression level of mRNA expressed from the gene serving as an internal standard is that of the HOTAIR region that is a lincRNA.
  • the higher the expression level the worse the prognosis.
  • the determination of small cell lung cancer with poor prognosis may be performed using the H / R ratio of the following formula.
  • H / R HOTAIR expression level / internal standard gene expression level
  • Detection of the expression level of HOTAIR and the internal standard gene can be performed by any known gene such as RT-PCR using various methods such as SYBR Green method or TaqMan method, Northern blot method, DNA chip (Affymetrix, etc.) It can be performed using expression quantification methods.
  • a real-time quantitative PCR method which is one of the RT-PCR methods, is preferable in that a very small amount of DNA can be detected with high sensitivity.
  • HOTAIR lamRNA
  • first strand cDNA is used as a template for PCR amplification with primers specific to HOTAIR cDNA.
  • Applied Biosystems High-Capacity cDNA Reverse Transcription Kit
  • real-time quantitative PCR for example, TaqMan (registered trademark) Gene Expression Assays provided by Applied Biosystems can be used.
  • Amplified products can be separated and quantified by electrophoresis, etc., but it is accurate and easy to quantify using real-time quantitative PCR instruments such as Applied Biosystems ABI PRISM 7000 Sequence Detection System and Roche LC480 system. Is preferable.
  • HOTAIR lincRNA
  • a primer for PCR usually about 10 to 30 nucleotide sequences sandwiching a polynucleotide portion of at least 50 bases, preferably 100 to 1,000 bases, of a polynucleotide of HOTAIR cDNA (SEQ ID NO: 1) or an internal standard gene.
  • a fragment consisting of As the probe a fragment consisting of at least 15 consecutive nucleotide sequences of a polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1 (HOTAIR cDNA) is usually used.
  • the probe base sequence is usually 15-30 bases, preferably 20-25 bases.
  • HOTAIR lincRNA
  • cDNA DNA array or Northern blot
  • the above primer or real-time quantitative PCR method is used. In some cases, the primer and the probe are used.
  • RNA is extracted from a surgical tumor tissue, and the expression status is confirmed by qRT-PCR using the above-mentioned primers of HOTAIR.
  • ⁇ -actin for tissues and GAPDH for cells as endogenous controls.
  • the method for detecting the expression level of HOTAIR includes, for example, the following steps.
  • SCLC small cell lung cancer
  • the steps d to e are used.
  • a step of amplification and detection of an internal standard gene may be included, and a step of comparing both expression levels may be added.
  • the poor-prognosis small cell lung cancer growth inhibitor of the present invention contains siRNA of HOTAIR that is lincRNA as an active ingredient.
  • This siRNA contains at least 19 consecutive bases in the base sequence of SEQ ID NO: 1 including the base sequences 801 to 819 of the base sequence of SEQ ID NO: 1, preferably 30 bases or less of the base sequence of SEQ ID NO: 1, Is an oligoribonucleotide corresponding to a base sequence of 27 bases or less, preferably 23 bases or less, its complementary oligoribonucleotide, or a double-stranded RNA comprising these.
  • the RNA fragment used in the present invention may be a sense RNA or a antisense RNA of the target RNA, but these are easily decomposed by RNase and are considered to be inferior in effectiveness. It is done.
  • This double-stranded RNA is usually used as a double strand by synthesizing both sense and antisense separately and then hybridizing them.
  • Oligoribonucleotides "corresponding" to these specific base sequences mean the RNA complementary to the portion corresponding to the specific base sequence of the lincRNA produced by transcription of this gene. It means that T in this specific DNA sequence is replaced with U.
  • the siRNA of the present invention may be a modified RNA that has been treated to prevent degradation by a nuclease, and may be, for example, a 2′-O-methylated or 4′-thiolated RNA aptamer.
  • an overhang sequence eg, dTdT, UU, UG, etc.
  • the small cell lung cancer growth inhibitor with poor prognosis may be a combination with other known tumor growth inhibitors and the like.
  • the agent for inhibiting small cell lung cancer growth of the present invention may be in the form of a kit containing such other drugs, or is pharmaceutically acceptable such as sterile isotonic saline, preservatives, buffering agents and the like. Media may be included.
  • siRNA may be encapsulated in a suitable carrier such as a liposome.
  • the poor prognosis small cell lung cancer growth inhibitor of the present invention is an injection kit for administering a mixture of the above-mentioned poor prognosis small cell lung cancer growth inhibitor formulated with a diluent, You may provide as kits, such as a kit for tablets for administering each formulated formulation.
  • the means for introducing siRNA into the cell is not particularly limited, and examples include calcium phosphate method, microinjection method, protoplast fusion method, electroporation, method using viral vector, etc.
  • Commercial transfection reagent based on liposome etc. Is easy to use.
  • siRNA siHOTAIR
  • it may be administered intravenously, and in the case of direct administration to the lesion, the affected area can be examined with an endoscope. In addition to administration, it may be done by inoculating the lesion at the time of surgery.
  • the small prognosis lung cancer cell growth inhibitor can be screened by the following method. Specifically, in the method of the present invention, human cultured small cell lung cancer cells are prepared, and the candidate drug and small cell lung cancer cells are contacted by culturing this cell line in the presence of the candidate drug. Inhibition or suppression of the expression of the lincRNA HOTAIR is performed to perform a primary screening of the candidate drug, and then the suppression of the proliferation and / or invasive ability of human cultured small cell lung cancer cells by the candidate drug is investigated. Perform next screening. As the SCLC cell used for screening, a cell line with a high HOTAIR RNA expression level is preferable. Examples of such an SCLC cell include the SBC-3 cell line.
  • SBC-3 cells are considered to correspond to a cell line of small lung cancer with poor prognosis because of the high expression level of HOTAIR RNA.
  • the degree of inhibition or suppression of the expression of HOTAIR which is a lincRNA, can be determined by a comparative experiment with a control to which no candidate drug is added. Expression levels are measured for total RNA or mRNA or poly A (+) RNA obtained from small cell lung cancer cell lines, or for cDNA synthesized from RNA by the reverse transcriptase-PCR (RT-PCR) method. It can be determined by a hybridization method using a radiolabeled probe (for example, Northern hybridization, Southern hybridization, DNA microarray, tissue microarray, etc.).
  • RT-PCR, PCR primers, and probes described above can be used.
  • this candidate drug Can be used as a small cell lung cancer metastasis inhibitor.
  • Example 1 The clinical specimens used in this example were prepared as follows. 35 SCLC tissue samples were obtained from multiple SCLC patients undergoing surgery at the Cancer Institute Hospital between 1995 and 2010 with written informed consent prior to surgery. It was. In addition, 16 non-cancerous tissue samples were obtained from the same patient. All specimens were immediately frozen in liquid nitrogen and stored at -80 ° C for RNA extraction. The SCLC tissue sample was collected as follows. Using lung tissue including lung cancer tissue submitted for rapid diagnosis, excise the cancerous part and non-cancerous part (area far enough from the cancerous part) (Fig. 1) and place it on a serum tube on ice. It was immediately put into liquid nitrogen and frozen.
  • the following examination was performed using the preserved tissue section at the time of rapid diagnosis of the case diagnosed as SCLC.
  • all the preserved tissue sections at the time of rapid diagnosis were sliced again with a cryostat, hematoxylin-eosin staining was performed, and it was confirmed later that the SCLC component was contained.
  • Table 1 shows the patient background and clinicopathological factors.
  • SCLC recurrence refers to a case in which new lesions were found in the lung and other organs during recurrence during the postoperative follow-up (up to about 15 years after surgery), and medical records and images were searched retrospectively.
  • the recurrent metastasis destination is described, but includes metastasis metastasized to a plurality.
  • follow-up results using medical records and follow-up survey results (about 15 years at the longest postoperatively) of Akenake Hospital's medical history room are shown.
  • HOTAIR expression was performed using quantitative real-time PCR (qRT-PCR) from the 35 SCLC samples collected and stored at the time when specimens were submitted to the pathology department for rapid diagnosis during surgery. I checked the level.
  • qRT-PCR was performed as follows. Total RNA was extracted from tissues and cells using RNeasy mini kit or RNeasy mini kit plus (Qiagen). CDNA was generated from 30 ng of total RNA using High Capacity RNA-to-cDNA (R) kit (AB, catalog number 4387406).
  • the obtained cDNA was subjected to PCR amplification for 45 cycles, followed by real-time PCR reaction using LightCycler (registered trademark) 480 SYBR Green I Master protocol (Roche, catalog number 4707516) and the following primers.
  • the expression level was examined. Each gene in each sample of a 96-well plate on the LightCycler (registered trademark) 480 real time PCR System (Roche) was tested three times.
  • the expression level of HOTAIR RNA was normalized with respect to the expression level of ⁇ -actin (ACTB) for tissue samples and xenografts.
  • ACTB ⁇ -actin
  • HOTAIR (F): 5'-GGTAGAAAAAGCAACCACGAAGC-3 '(SEQ ID NO: 4)
  • HOTAIR (R): 5'-ACATAAACCTCTGTCTGTGAGTGCC-3 '(SEQ ID NO: 5)
  • ACTB (F): 5'-AGAAAATCTGGCACCACACC-3 '(SEQ ID NO: 6)
  • ACTB (R): 5'-AGAGGCGTACAGGGATAGCA-3 '(SEQ ID NO: 7)
  • the HOTAIR / ACTB ratio was examined in 35 SCLC tissues and 15 non-cancerous tissues in the same subject group (FIG. 2).
  • a level where the HOTAIR / ACTB ratio was higher than 1.368 was regarded as high HOTAIR expression. According to this criteria, 12 out of 35 SCLC patients were classified as having high HOTAIR expression and 23 were classified as low.
  • the clinicopathological factors of these two groups are shown in Table 1.
  • the high HOTAIR expression group showed more recurrence and death than the low HOTAIR expression group.
  • Example 3 The cell line used in this example was prepared as follows. SCLC cell lines COLO-668, COR-L51, COR-L88, and DMS-79 were obtained from ECACC (The European Collection of Cell Cultures). SCLC cell lines DMS-53, LU-134A, MS-1, SBC-3, SBC-5, SBC-1, A549 and MRC-5 are either JCRB (Japanese Collection of Research Bio-resources) or RIKEN Obtained from the BioResource Center (BRC). These cell lines were cultured in Dulbecco's modified Eagle medium (DMEM, Nacalai Tesque, catalog number 08488-55, 500 ml) in a 37 ° C, 5% CO 2 incubator.
  • DMEM Dulbecco's modified Eagle medium
  • This Dulbecco's modified Eagle medium consists of 5.0 ml of 200 mM L-alanyl-L-glutamine solution (Nacalai Tesque catalog number 04260-64), 5.5 ml of antibiotic antifungal mixed stock solution (Nacalai Tesque catalog number 02892-54), And 50 ml of fetal bovine serum (Biowest catalog number S1560).
  • RNA interference experiments with HOTAIR were performed as follows. Using Lipofectamine TM RNAiMAX (Invitrogen, catalog number 13778-075), 20 nM siRNA targeting HOTAIR was introduced into the cells according to the manufacturer's instructions. The efficiency of this introduction is determined by introducing a labeled positive control (Blex-IT TM Alexa Fluor® red fluorescent oligo (Invitrogen, Catalog No. 14750-100)), and then placing the cells in a humidified environment containing 5% CO 2. And incubated at 37 ° C. for 72 hours, and then evaluated using a fluorescence microscope (Leica DMIRE2).
  • RNA interference was similarly performed for the GFP gene as a negative control. Quantitative RT-PCR was performed in the same manner as in Example 1.
  • siHOTAIR Sense: 5′-GAACGGGAGUACAGAGAGAUU-3 ′ (corresponding to positions 801 to 819 of SEQ ID NO: 10 and SEQ ID NO: 1)
  • the expression level of HOTAIR RNA is shown in FIG. 4B. # 1-3 It can be seen that the introduction of siHOTAIR decreased the expression level of HOTAIR RNA. Furthermore, SBC-3 cell line after introduction of # 1-3 siHOTAIR (below) was cultured in Dulbecco's modified Eagle medium (DMEM, Nacalai Tesque catalog number 08488-55, 500 ml) in a 37 ° C, 5% CO2 incubator. . This Dulbecco's modified Eagle medium contains 5.0 ml of 200 mM L-alanyl-L-glutamine solution (Nacalai Tesque catalog number 04260-64) and 50 ml of fetal calf serum (Biowest catalog number S1560).
  • DMEM Dulbecco's modified Eagle medium
  • This Dulbecco's modified Eagle medium contains 5.0 ml of 200 mM L-alanyl-L-glutamine solution (Nacalai Tesque catalog number 04260-64) and 50 m

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Abstract

[Problème] Dans le cancer du poumon à petites cellules (SCLC), il existe un type ayant un faible pronostic et un type ayant un bon pronostic. Il a été demandé de détecter le cancer du poumon à petites cellules à un stade précoce et d'établir un procédé de traitement pour le cancer du poumon à petites cellules. La présente invention concerne : un procédé de test qui peut détecter le cancer du poumon à petites cellules ayant un faible pronostic ; un moyen de traitement du cancer du poumon à petites cellules ayant un faible pronostic ; et un procédé de criblage pour un médicament pour traiter le cancer du poumon à petites cellules ayant un faible pronostic. [Solution] Il a été trouvé que HOTAIR (pour lequel l'ADNc comprend la séquence nucléotidique représentée par SEQ ID NO : 1), qui est un grand ARN intergénique non codant (linc), est hautement exprimé dans le cancer du poumon à petites cellules ayant un faible pronostic. La présente invention est un procédé de diagnostic pour déterminer si oui ou non le cancer du poumon à petites cellules est un cancer ayant un faible pronostic, dans lequel le pronostic du cancer du poumon à petites cellules est déterminé comme étant plus faible quand la quantité de HOTAIR, qui est un ARNlinc, exprimé dans un échantillon du cancer du poumon à petites cellules est plus élevé. De plus, un ARNsi qui peut inhiber la prolifération du cancer du poumon à petites cellules, dans lequel HOTAIR est hautement exprimé, est découvert.
PCT/JP2013/066947 2012-06-22 2013-06-20 Procédé de test et moyens de traitement pour le cancer du poumon à petites cellules ayant un faible pronostic WO2013191242A1 (fr)

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WO2023074135A1 (fr) * 2021-11-01 2023-05-04 国立研究開発法人国立がん研究センター Procédé et kit de réactifs pour aider à déterminer le pronostic du cancer pulmonaire

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JP6597316B2 (ja) * 2016-01-06 2019-10-30 コニカミノルタ株式会社 画像処理装置及びプログラム
EP3707259A4 (fr) * 2017-11-12 2021-08-11 The Regents of the University of California Arn non codant pour la détection du cancer

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DATABASE GENBANK 24 February 2012 (2012-02-24), "Definition: Homo sapiens HOX transcript antisense RNA (non-protein coding) (HOTAIR), antisense RNA", retrieved from http://www.ncbi.nlm.nih.gov/nuccore/ NR_003716.2 accession no. R_ 003716.2 *
HIROSHI ONO ET AL.: "Haishosaibogan ni Okeru HOTAIR no Hatsugen wa Jutsugo Saihatsu to Kanren shiteiru", NIPPON BYORI GAKKAISHI, vol. 101, no. 1, 26 March 2012 (2012-03-26), pages 258 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023074135A1 (fr) * 2021-11-01 2023-05-04 国立研究開発法人国立がん研究センター Procédé et kit de réactifs pour aider à déterminer le pronostic du cancer pulmonaire

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