WO2021203798A1 - 剪接因子prpf31抑制剂用于制备药物的用途 - Google Patents
剪接因子prpf31抑制剂用于制备药物的用途 Download PDFInfo
- Publication number
- WO2021203798A1 WO2021203798A1 PCT/CN2021/073519 CN2021073519W WO2021203798A1 WO 2021203798 A1 WO2021203798 A1 WO 2021203798A1 CN 2021073519 W CN2021073519 W CN 2021073519W WO 2021203798 A1 WO2021203798 A1 WO 2021203798A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prpf31
- cancer
- inhibitor
- cells
- use according
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 30
- 108010039259 RNA Splicing Factors Proteins 0.000 title claims abstract description 19
- 102000015097 RNA Splicing Factors Human genes 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title abstract description 11
- 101150027683 prpf31 gene Proteins 0.000 title 1
- 101000610557 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp31 Proteins 0.000 claims abstract description 78
- 102100040118 U4/U6 small nuclear ribonucleoprotein Prp31 Human genes 0.000 claims abstract description 76
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 59
- 201000011510 cancer Diseases 0.000 claims abstract description 53
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 238000004393 prognosis Methods 0.000 claims abstract description 8
- 230000005907 cancer growth Effects 0.000 claims abstract description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 19
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 108020004459 Small interfering RNA Proteins 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 230000009286 beneficial effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000007523 nucleic acids Chemical group 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 229920002477 rna polymer Polymers 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 66
- 210000001519 tissue Anatomy 0.000 description 16
- 230000012010 growth Effects 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 10
- 230000029087 digestion Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 229950010131 puromycin Drugs 0.000 description 7
- 210000001324 spliceosome Anatomy 0.000 description 5
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 230000003698 anagen phase Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- 108700024394 Exon Proteins 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 230000003021 clonogenic effect Effects 0.000 description 3
- 238000003235 crystal violet staining Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 239000012096 transfection reagent Substances 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- 108091092724 Noncoding DNA Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102000004598 Small Nuclear Ribonucleoproteins Human genes 0.000 description 2
- 108010003165 Small Nuclear Ribonucleoproteins Proteins 0.000 description 2
- 102000018686 U4-U6 Small Nuclear Ribonucleoprotein Human genes 0.000 description 2
- 108010091808 U4-U6 Small Nuclear Ribonucleoprotein Proteins 0.000 description 2
- 201000005969 Uveal melanoma Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000030173 low grade glioma Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000003153 stable transfection Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000008836 DNA modification Effects 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101001105683 Homo sapiens Pre-mRNA-processing-splicing factor 8 Proteins 0.000 description 1
- 101000587442 Homo sapiens Serine/arginine-rich splicing factor 6 Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100021231 Pre-mRNA-processing-splicing factor 8 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108020005093 RNA Precursors Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000018165 U1 Small Nuclear Ribonucleoprotein Human genes 0.000 description 1
- 108010091281 U1 Small Nuclear Ribonucleoprotein Proteins 0.000 description 1
- 102000006986 U2 Small Nuclear Ribonucleoprotein Human genes 0.000 description 1
- 108010072724 U2 Small Nuclear Ribonucleoprotein Proteins 0.000 description 1
- 102000006837 U5 Small Nuclear Ribonucleoprotein Human genes 0.000 description 1
- 108010086857 U5 Small Nuclear Ribonucleoprotein Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- -1 glidants Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000006197 histone deacetylation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/13—Nucleic acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention belongs to the technical field of new targets for cancer treatment, and specifically relates to the use of splicing factor PRPF31 inhibitors for preparing medicines.
- cancers in medicine. Carrying out precise targeted drug treatments, cancer patients continue to be cured.
- targets and the endless stream of new targeted drugs developed and put into use, including lung cancer, breast cancer, colorectal cancer, leukemia, lymphoma, thyroid cancer, melanoma, kidney cancer, liver cancer, gastric cancer, Multiple myeloma, pancreatic cancer and other cancer patients bring hope. Even so, cancer treatment is still a big problem, so the discovery of new cancer treatment targets is of great significance for cancer treatment.
- Splicing is an important modification process after gene transcription. Its main function is to remove introns in immature mRNA and connect exons. Splicing mainly occurs in the spliceosome of the nucleus.
- the spliceosome contains 5 small nuclear ribonucleoproteins (U1, U2, U4, U5 and U6 snRNP) and more than 150 proteins.
- U1, U2, U4, U5 and U6 snRNP small nuclear ribonucleoproteins
- Auxiliary splicing factors can push the spliceosome to decide whether to leave or remove some exons by recognizing the splicing site. , This is the mechanism of alternative splicing.
- Splicing is ubiquitous in eukaryotic multicellular organisms, and it plays an important role in a variety of physiological processes. Splicing factors play a central role in the regulation of alternative splicing by interacting with sequence elements on the RNA precursor. Splicing abnormality is one of the main causes of human genetic diseases, and it has been proved to be closely related to the occurrence, development, and drug tolerance of cancer. Studies have found that alternative splicing regulated by the splicing factor SRSF6 can promote the growth of colon cancer cells (Wan L, et al. Gut 2017; 0:1-12). Another study found that in cervical cancer cells, PRPF8 affects cell growth by participating in mitochondrial autophagy.
- PRPF31 a pre-mRNA processing factor that exists in the nucleus and spliceosomes, is a component of the U4/U6.U5 trisnRNP (small nuclear ribonucleoprotein) subunit of the spliceosome and participates in the regulation of alternative splicing.
- PRPF31 is widely distributed in various tissues and organs, and the expression of cancer tissues is usually higher than that of normal tissues. Previous studies have found that mutations in PRPF31 can cause retinitis pigmentosa. Recent studies have also found that PRPF31 is directly involved in the mitosis of Drosophila chromosomes (Pellacani et al. eLife 2018; 7: e40325). There is no report about the treatment of cancer by inhibiting PRPF31.
- the present invention provides the application of splicing factor PRPF31 inhibitors in the prevention and treatment of cancer, and provides a basis for the development of drugs for the treatment of cancer.
- the present invention provides the use of splicing factor PRPF31 inhibitors for the preparation of medicines for the prevention and/or treatment of cancer.
- the splicing factor PRPF31 includes the normal splicing factor PRPF31 or its mutants (a small part of the sequence has been mutated, deleted or increased, etc.).
- the amino acid sequence of the normal splicing factor PRPF31 is as follows: NCBI Reference Sequence: NP_056444.3:
- the present invention first discovered that the splicing factor PRPF31 can be used as a cancer treatment target. Therefore, substances that inhibit this target can be used to treat cancer.
- the splicing factor PRPF31 inhibitor of the present invention is a substance that inhibits the activity or expression of PRPF31.
- the splicing factor PRPF31 inhibitor of the present invention can inhibit the expression of PRPF31 protein or inhibit the activity/function of PRPF31 by the following means, thereby being used for the prevention and/or treatment of cancer:
- DNA modification including but not limited to DNA promoter region methylation
- histone modification including but not limited to histone deacetylation
- PRPF31 neutralizing antibody, blocking antibody or blocking peptide
- the PRPF31 inhibitor includes but is not limited to small molecule organics, small molecule inorganics, anti-PRPF31 antibodies, nucleic acid fragments or polypeptides that can specifically bind to PRPF31 and inhibit its activity.
- the PRPF31 inhibitor also includes inhibitor precursors.
- the PRPF31 inhibitor may be selected from artificially synthesized small interfering ribonucleic acid (siRNA) or short hairpin ribonucleic acid (shRNA).
- siRNA small interfering ribonucleic acid
- shRNA short hairpin ribonucleic acid
- the cancer includes all kinds of cancers, such as non-small cell lung cancer, breast cancer, colorectal cancer, osteosarcoma, or liver cancer.
- the PRPF31 inhibitor can inhibit the growth of cancer and is beneficial to the prognosis of cancer, thereby preventing, improving or treating cancer.
- the present invention also provides the use of the composition containing the splicing factor PRPF31 inhibitor for the preparation of a medicine for the prevention and/or treatment of cancer.
- composition includes a PRPF31 inhibitor (preferably, a therapeutically effective amount of the inhibitor) and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutically acceptable carriers or excipients such as diluents, binders, disintegrants, glidants, lubricants, flavoring agents, inclusion materials, adsorbent materials, and the like.
- the form of the composition is a medicine, a dietary supplement or a health care product composition.
- the target organ or tissue that the PRPF31 inhibitor acts on is an organ or tissue that expresses PRPF31 in a mammal or a human.
- the PRPF31 inhibitor of the present invention prevents or treats cancer
- it can be used alone, in combination with other drugs, or used in a compound preparation together with other drugs, all of which can achieve the purpose of preventing or treating cancer.
- PRPF31 in the present invention can inhibit the growth of a variety of cancers. It shows that PRPF31 inhibitors can be used in the treatment of cancer and have the prospect of developing drugs.
- the present invention discovered for the first time that the splicing factor PRPF31 can be used as a cancer treatment target. Further studies have shown that knocking down PRPF31 and stably transfecting shPRPF31 is not conducive to the growth of cancer, and PRPF31 is found in various normal tissues. The distribution and high expression in cancer tissues are not conducive to the prognosis of cancer. Therefore, PRPF31 inhibitors can obviously be used for the prevention and treatment of cancer and have the prospect of developing drugs.
- Figure 1 is the Western blot detection of PRPF31 expression after non-small cell lung cancer NCI-H460 cells were transfected with different concentrations of NC or siPRPF31, 24h after harvesting the cells;
- Figure 2 is a fluorescence spectrophotometer detection diagram of Luciferase enzyme expression in non-small cell lung cancer NCI-H460 transfected with shNC or shPRPF31;
- Figure 3 is a Westren Blot detection diagram of non-small cell lung cancer NCI-H460 cells stably transfected with shNC or shPRPF31, and PRPF31 expression after the cells are harvested;
- Figure 4 is a graph showing the cloning ability of non-small cell lung cancer NCI-H460 cells transfected with different concentrations of NC or siPRPF31 after 24 hours of digestion cell plating;
- Figure 5 is a graph showing the cloning ability of non-small cell lung cancer NCI-1299 cells respectively transfected with NC, siPRPF31 or only with transfection reagent, after 24 hours of digestion cell plating;
- Figure 6 is a graph showing the cloning ability of a variety of cancer cells transfected with different concentrations of shNC or shPRPF31, 36 hours after digestion of the cell plate;
- Figure 7 is a comparison diagram of PRPF31 expression in various cancer tissues and corresponding normal tissues
- Figure 8 is a graph showing the relationship between the high expression of PRPF31 in a variety of cancer tissues and the prognosis of patients.
- siPRPF31 knockdown verification A brief description is as follows, artificially synthesized 3 independent sequences of siPRPF31, respectively, the sequences are: siPRPF31#1: GCTACGAACTGAAGGATGA; siPRPF31#2: GCCAAGCTATGGGATAGTA; siPRPF31#3: CAAGCAAGCCAAAGCTTCA.
- NCI-H460 cells Take logarithmic growth phase of non-small cell lung cancer NCI-H460 cells, digest with 0.25% trypsin, discard the digestion solution, gently pipette to mix with complete medium, count, and adjust the cell density to 5 ⁇ 7.5 ⁇ 10 5 cells/mL , 2mL was inoculated in a 6-well culture plate, and the NC or siPRPF31 mixture 100nM, 150nM, 200nM was transfected respectively on the second day, and the cells were harvested 24h after transfection. Western blotting was used to detect whether PRPF31 was successfully knocked down.
- shPRPF31#1 GCTACGAACTGAAGGATGA
- shPRPF31#2 GCCAAGCTATGGGATAGTA.
- the cells were digested, counted, and the cell density was adjusted to 1 ⁇ 10 3 cells/ mL and 2 mL were seeded in a 6-well plate and grown for 2 weeks.
- the clonogenic ability of the cells was observed using crystal violet staining.
- the best action time of Puromycin is generally between 1 and 3 days.
- the optimal antibiotic concentration refers to the lowest screening concentration that kills all cells within 1 to 3 days from the beginning of antibiotic screening.
- Day 2 After 36 hours after the virus infects the cells, the cells are digested to a density of 1 ⁇ 10 3 cells/mL, spread on a 6-well culture plate, and cultured with a selection medium containing the corresponding optimal concentration of Puromycin for about 14 days. Use Crystal violet staining was used to observe the clonogenic ability of cells.
- PRPF31 in various normal tissues and cancer tissues and the high expression of PRPF31 are not conducive to the prognosis of some cancer patients.
- the number of NCI-H460 cells transfected with siPRPF31 was significantly less than the number of NCI-H460 cells transfected with NC, and was consistent with the transfection efficiency of siPRPF31 in Figure 1.
- the number of NCI-1299 cells transfected with siPRPF31 was significantly less than the number of NCI-H1299 cells transfected with NC and transfection reagent. It shows that knocking down PRPF31 is not conducive to the growth of non-small cell lung cancer NCI-H460 and NCI-H1299 ( Figure 4 and Figure 5).
- Cancer cells stably transfected with shPRPF31 including: non-small cell lung cancer (NCI-H460, NCI-H1299, A549), breast cancer (MDA-MB-231, MCF-7, MDF-MCF-7), colon cancer (HCT116) , HT29, SW480), osteosarcoma (HOS, U2-OS), liver cancer (LM3, HepG2), compared with the corresponding transfected shNC, the number of cells was significantly reduced. It shows that stably transfected shPRPF31 is not conducive to the growth of a variety of cancers (Figure 6).
- PRPF31 in various normal tissues and cancer tissues and the high expression of PRPF31 are not conducive to the prognosis of some cancer patients.
- PRPF31 The expression level of PRPF31 in most cancer tissues is higher than that of the corresponding normal tissues ( Figure 7), suggesting that the splicing factor PRPF31 may be an important molecule indispensable for cancer growth and development.
- KICH renal chromophobe cell carcinoma
- LAML acute myeloid leukemia
- LGG brain low-grade glioma
- LIHC hepatocellular carcinoma
- MEO mesothelioma
- PRAD prostate cancer
- SARC sarcoma
- UVM uveal melanoma
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
提供了一种剪接因子PRPF31抑制剂用于制备预防和/或治疗癌症的药物的用途。剪接因子PRPF31可以作为癌症治疗靶点,敲低PRPF31或稳定转染shPRPF31显著抑制癌症的生长,并且PRPF31在多数癌组织中表达量高于相对应的正常组织,PRPF31高表达使癌症的预后不良。
Description
本发明属于癌症治疗新靶点技术领域,具体涉及剪接因子PRPF31抑制剂用于制备药物的用途。
背景内容
近十几年来癌症的发病率、死亡率均呈持续上升态势,已成为严重威胁人类健康的主要公共卫生问题之一。癌症,长期以来因其很难治愈又被称为“绝症”或“不治之症”,许多人往往“谈癌色变”。因为一旦患癌,就意味着要经历手术切除、放疗或化疗的痛苦折磨,而且还难以逾越高死亡率的禁区。2020年全世界的癌症发病人数将从2001年的1000万增加到1500万,癌症死亡人数将由2001年的600万上升至1000万。随着近年来医疗科技的飞速发展,目前癌症治疗不再是简单粗暴的无差别打击,科学家们寻找到癌细胞和正常细胞之间更多的不同点,医学上称之为“靶点”,进行精准的靶向药物治疗,不断有癌症患者被治愈。多种癌症“靶点”的发现和层出不穷的新靶向药物的研发及投入使用,为肺癌、乳腺癌、结直肠癌、白血病、淋巴瘤、甲状腺癌、黑色素瘤、肾癌、肝癌、胃癌、多发性骨髓瘤、胰腺癌等多种癌症患者带来了希望。即使如此,癌症的治疗仍是一大难题,所以发现新的癌症的治疗靶点对于癌症的治疗具有重要意义。
剪接是基因转录后重要的修饰过程,主要作用是将不成熟mRNA中的内含子切除,将外显子连接起来。剪接主要发生在细胞核的剪接体,剪接体包含5个小核内核糖核蛋白(U1,U2,U4,U5和U6 snRNP)以及150个以上的蛋白质。在剪接过程中外显子的识别主要是由剪接位点介导,因此剪接过程是多变的,辅助性剪接因子可以推动剪接体通过对剪接位点的识别决定留下还是切除某些外显子,这就是选择性剪接的发生机制。可变剪接(Alternative Splicing,AS)普遍存在于真核多细胞生物,在多种生理过程中发挥着重要功能。剪接因子通过与RNA前体上的序列元件相互作用,在可变剪接调控中发挥核心作用。剪接异常是导致人类遗传疾病的主要原因之一,并被证实与癌症发生、发展、药物耐受等紧密相关。研究发现剪接因子SRSF6调节的选择性剪接可以促进结肠癌细胞的生长(Wan L,et al.Gut 2017;0:1-12)。另有研究发现,在宫颈癌细胞中,PRPF8通过参与线粒体自噬影响细胞的生长。
PRPF31,一种存在于细胞核和剪接小体的pre-mRNA加工因子,是剪接体U4/U6.U5 trisnRNP(small nuclear ribonucleoprotein)亚基的部件,参与可变剪接调控。 PRPF31广泛分布于各个组织、器官,通常癌组织表达高于正常组织。前期研究发现,PRPF31突变可导致视网膜色素变性。近期亦有研究发现,PRPF31直接参与果蝇染色体的有丝分裂(Pellacani et al.eLife 2018;7:e40325)。目前没有关于通过抑制PRPF31治疗癌症的任何报道。
发明内容
发明目的:为解决上述问题,本发明提供了剪接因子PRPF31抑制剂在预防和治疗癌症方面的应用,为开发治疗癌症的药物提供依据。
技术方案:为达到上述发明目的,本发明技术方案如下:
一方面,本发明提供了剪接因子PRPF31抑制剂用于制备药物的用途,所述药物用于预防和/或治疗癌症。
所述剪接因子PRPF31包括正常的剪接因子PRPF31或其突变体(序列中有一小部分发生了变异、缺失或者增加等),正常剪接因子PRPF31的氨基酸序列如下NCBI Reference Sequence:NP_056444.3所示:
NCBI Reference Sequence:NP_056444.3
本发明首先发现剪接因子PRPF31可以作为癌症治疗靶点,因此,抑制该靶点的物质可以用于治疗癌症,本发明所述剪接因子PRPF31抑制剂为抑制PRPF31活性或表达的物质。
本发明所述剪接因子PRPF31抑制剂可以通过以下手段抑制PRPF31蛋白表达或抑制PRPF31活性/功能,从而用于预防和/或治疗癌症:
靶向PRPF31mRNA促进其降解的siRNA和/或shRNA;
靶向PRPF31 mRNA的3’非编码区(3’UTRs)或5’非编码区(5’UTRs),抑制其蛋白翻译的miRNA;
通过基因敲除(Knockout)技术敲除PRPF31;
通过调控DNA修饰(包括但不局限于DNA启动子区域甲基化)和/或组蛋白修饰(包括但不局限于组蛋白去乙酰化),从而抑制PRPF31基因转录;
通过抑制转录因子与PRPF31启动子和/或增强子结合,从而抑制PRPF31转录;
靶向PRPF31蛋白,抑制其发挥功能的阻断剂、拮抗剂或抑制剂;
抑制PRPF31基因或蛋白表达的抑制剂;
PRPF31的中和抗体、封闭抗体或阻断肽;
等,但是并不局限于上述手段。
作为进一步选择:
所述PRPF31抑制剂包括单不限于小分子有机物、小分子无机物、抗PRPF31抗体、能与PRPF31特异性结合并抑制其活性的核酸片段或多肽。
所述PRPF31抑制剂还包括抑制剂前体。
例如,所述PRPF31抑制剂可以选自人工合成的小干扰核糖核酸(siRNA)或短发夹核糖核酸(shRNA)。
所述癌症包括所有种类的癌症,例如非小细胞肺癌、乳腺癌、结直肠癌、骨肉瘤或肝癌等。
所述PRPF31抑制剂能够抑制癌症的生长,并且有利于癌症的预后,从而预防、改善或治疗癌症。
另一方面,本发明还提供了包含剪接因子PRPF31抑制剂的组合物用于制备药物的用途,所述药物用于预防和/或治疗癌症。
所述组合物包括PRPF31抑制剂(较佳地,为治疗有效量的抑制剂)以及药学上可接受的载体或赋形剂。
所述药学上可接受的载体或赋形剂,例如稀释剂、黏合剂、崩解剂、助流剂、润滑剂、矫味剂、包合材料、吸附材料等。
所述的组合物的形式为药物、饮食补充剂或保健品组合物。
所述PRPF31抑制剂作用的靶器官或组织为哺乳动物或人体内表达PRPF31的器官组织。
本发明所述PRPF31抑制剂在预防或治疗癌症时,可以单独使用,也可以与其他药物配合同时使用,或者与其他药物一起制成复方制剂使用,都可以达到预防或治疗癌症的目的。
本发明所述抑制PRPF31可以抑制多种癌症的生长。表明PRPF31抑制剂可用于癌症的治疗,具有开发药物的前景。
有益效果:相对于现有技术,本发明首次发现了剪接因子PRPF31可以作为癌症治疗靶点,通过进一步研究表明,敲低PRPF31和稳定转染shPRPF31不利于癌症的生长,并且PRPF31在各种正常组织和癌组织中的分布以及高表达不利于癌症的预后。因此,PRPF31抑制剂明显可用于癌症的预防和治疗,具有开发药物的前景。
图1是非小细胞肺癌NCI-H460细胞分别转染不同浓度的NC或者siPRPF31,24h收细胞后PRPF31表达的Westren Blot检测图;
图2是转染shNC或者shPRPF31的非小细胞肺癌NCI-H460中,Luciferase酶表达的荧光分光光度计检测图;
图3是非小细胞肺癌NCI-H460细胞稳定转染shNC或者shPRPF31,收细胞后PRPF31表达的Westren Blot检测图;
图4是非小细胞肺癌NCI-H460细胞分别转染不同浓度的NC或者siPRPF31,24h之后消化细胞铺板的克隆形成能力图;
图5是非小细胞肺癌NCI-1299细胞分别转染NC,siPRPF31或者只加转染试剂,24h之后消化细胞铺板的克隆形成能力图;
图6是多种癌细胞分别转染不同浓度的shNC或者shPRPF31,36h之后消化细胞铺板的克隆形成能力图;
图7是PRPF31在多种癌组织和相应正常组织中的表达量比较图;
图8是多种癌组织中PRPF31高表达与患者预后关系图。
下面结合附图和具体实例,进一步阐明本发明,应理解这些实例仅用于说明本发明而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例
一、试验方法
1.siPRPF31、shPRPF31敲低验证以及构建shPRFF31稳定株
1.1 siPRPF31敲低验证。简述如下,人工分别合成siPRPF31独立的3条序列,序列分别为:siPRPF31#1:GCTACGAACTGAAGGATGA;siPRPF31#2:GCCAAGCTATGGGATAGTA;siPRPF31#3:CAAGCAAGCCAAAGCTTCA。取对数生长期的非小细胞肺癌NCI-H460细胞,0.25%胰蛋白酶消化,弃消化液,用完全培养基轻轻吹打混匀,计数,调整细胞密度至5~7.5×10
5cells/mL,2mL接种于6孔培养板中,于第二日分别转染NC或siPRPF31混合物100nM,150nM,200nM,转染24h后收细胞,利用免疫印迹的方法检测PRPF31是否敲低成功。
1.2 shPRPF31稳定株的构建。简述如下,人工构建含有luciferase的shPRPF31两条(抗嘌呤霉素),序列分别为:shPRPF31#1:GCTACGAACTGAAGGATGA;shPRPF31#2:GCCAAGCTATGGGATAGTA。取对数生长期的非小细胞肺癌NCI-H460细胞,0.25%胰蛋白酶消化,弃消化液,用完全培养基轻轻吹打混匀,计数,调整细胞密度至5~7.5×10
5cells/mL,2mL接种于6孔培养板中,筛选出NCI-H460抗嘌呤霉素的最佳浓度。用相同的方法将NCI-H460细胞密度调整至1~1.25×10
5cells/mL,接种于48孔板,贴壁后(12h)转染shNC或者shPRPF31,36h后将培养基换成含有相应最佳浓度的嘌呤霉素的筛选培养基,维持此条件继续培养或传代扩增,建立稳定敲低PRPF31的细胞株,然后利用免疫印迹的方法检测PRPF31是否稳定敲低。
1.3 shPRPF31成功转染NCI-H460细胞的测试。简述如下,用上述相同的方法将NCI-H460细胞密度调整至1~1.25×10
5cells/mL,接种于48孔板,贴壁后(12h)转染shNC或者shPRPF31,36h后取出一部分,使用luciferase检测试剂盒,参照说明书,应用荧光分光光度计于560nM波长处检测吸光度。
2.敲低PRPF31不利于非小细胞肺癌NCI-H460以及NCI-H1299的生长
2.1敲低PRPF31不利于非小细胞肺癌NCI-H460的生长。简述如下,取对数生长期的非小细胞肺癌NCI-H460细胞,0.25%胰蛋白酶消化,弃消化液,用完全培养基轻轻吹打混匀,计数,调整细胞密度至5~7.5×10
5cells/mL,2mL接种于6孔培养板中,于第二日分别转染NC或siPRPF31混合物100nM,150nM,200nM,转染24h后消化细胞,计数,调整细胞密度至1×10
3cells/mL,2mL接种于6孔板中,生长2周,使用结晶紫染色观察细胞的克隆形成能力。
2.2敲低PRPF31不利于非小细胞肺癌NCI-H1299的生长。简述如下,取对数生长期的非小细胞肺癌NCI-H460细胞,0.25%胰蛋白酶消化,弃消化液,用完全培养基轻轻吹打混匀,计数,调整细胞密度至2.5~5×10
5cells/mL,2mL接种于6孔培养板中,于第二日分别转染NC,siPRPF31或者单独使用转染试剂,转染24h后消化细胞,计数,调整细胞密度至1×10
3cells/mL,2mL接种于6孔板中,生长2周,使用结晶紫染色观察细胞的克隆形成能力。
3.稳定转染shPRPF31不利于多种癌症的生长
3.1筛选不同癌细胞的最佳嘌呤霉素浓度。简述如下,
A.6孔培养板内以合适的细胞密度铺板,以备梯度实验,细胞孵育过夜;
B.配制适量含不同浓度Puromycin的新鲜培养基(0、0.5、1、2、4、8μg/mL);
C.将6孔培养板中旧培养基替换为筛选培养基,继续孵育细胞;
D.约2~3天更换新鲜的筛选培养基,每日监测细胞,观察存活细胞比例。
Puromycin的最佳作用时间一般在1~3天之间。最佳抗生素使用浓度指从抗生素筛选开始1~3天内杀死所有细胞的最低筛选浓度。
3.2稳定转染shPRPF31的癌细胞的克隆形成能力。简述如下,
Day 0:在48孔培养板内以合适的细胞密度铺板,孵育过夜;
Day 1:按照测定的MOI和细胞感染实验方法,感染细胞;
Day 2:病毒感染细胞后36h后消化细胞至密度为1×10
3cells/mL,铺于6孔培养板中,用含有相应的最佳浓度的Puromycin的筛选培养基培养至14天左右,使用结晶紫染色观察细胞的克隆形成能力。
4.PRPF31在各种正常组织和癌组织中的分布以及高表达PRPF31不利于一些癌症病人的预后。
使用GEPIA数据库在线查询得知。
二、试验结果
1.siPRPF31、shPRPF31敲低以及构建shPRFF31稳定株验证。
非小细胞肺癌NCI-H460转染siPPRF31之后与转染NC相比,PRPF31的表达量明显下降,且最佳敲低浓度为150nM,说明PRPF31敲低成功(图1)。稳定转染shPRPF31的非小细胞肺癌NCI-H460与相同条件下转染shNC的NCI-H460细胞相比,PRPF31的表达量明显降低,说明构建shPRPF31稳定株成功(图2)。分别感染 shNC,shPRPF31,shPRPF31#2的NCI-H460细胞的荧光强度明显强于正常的NCI-H460细胞,说明NCI-H460转染病毒成功(图3)。
2.敲低PRPF31不利于非小细胞肺癌NCI-H460以及NCI-H1299的生长
转染siPRPF31的NCI-H460的细胞的数目明显少于转染NC的NCI-H460的数目,并且与图1中siPRPF31的转染效率一致。转染siPRPF31的NCI-1299的细胞的数目明显少于转染NC以及转染试剂的NCI-H1299的数目。说明敲低PRPF31不利于非小细胞肺癌NCI-H460以及NCI-H1299的生长(图4和图5)。
3.稳定转染shPRPF31不利于多种癌症的生长
稳定转染shPRPF31的癌细胞,包括:非小细胞肺癌(NCI-H460、NCI-H1299、A549),乳腺癌(MDA-MB-231、MCF-7、MDF-MCF-7),结肠癌(HCT116、HT29、SW480),骨肉瘤(HOS、U2-OS),肝癌(LM3、HepG2),与相对应的转染shNC相比,细胞数目明显减少。说明稳定转染shPRPF31不利于多种癌症的生长(图6)。
4.PRPF31在各种正常组织和癌组织中的分布以及高表达PRPF31不利于一些癌症病人的预后。
PRPF31在多数癌组织中表达量高于相对应的正常组织(图7),提示剪接因子PRPF31可能是癌症生长、发展不可或缺的重要分子。另外,如图8所示,在肾嫌色细胞癌(KICH)、急性髓系白血病(LAML)、脑低级别胶质瘤(LGG)、肝细胞癌(LIHC)、间皮瘤(MESO)、前列腺癌(PRAD)、肉瘤(SARC)、葡萄膜黑色素瘤(UVM)中高表达PRPF31不利于病人的预后。
Claims (9)
- 剪接因子PRPF31抑制剂用于制备药物的用途,所述药物用于预防和/或治疗癌症。
- 根据权利要求1所述的用途,其特征在于,所述PRPF31抑制剂为抑制PRPF31活性或表达的物质。
- 根据权利要求1所述的用途,其特征在于,所述PRPF31抑制剂包括小分子有机物、小分子无机物、抗PRPF31抗体、能与PRPF31特异性结合并抑制其活性的核酸片段或多肽。
- 根据权利要求1所述的用途,其特征在于,所述PRPF31抑制剂包括抑制剂前体。
- 根据权利要求1所述的用途,其特征在于,所述PRPF31抑制剂选自人工合成的小干扰核糖核酸(siRNA)或短发夹核糖核酸(shRNA)。
- 根据权利要求1所述的用途,其特征在于,所述癌症包括非小细胞肺癌、乳腺癌、结直肠癌、骨肉瘤或肝癌。
- 根据权利要求1所述的用途,其特征在于,所述PRPF31抑制剂能够抑制癌组织的生长,并且有利于癌症的预后。
- 包含剪接因子PRPF31抑制剂的组合物用于制备药物的用途,所述药物用于预防和/或治疗癌症。
- 如权利要求8所述的用途,其特征在于,所述组合物包括PRPF31抑制剂以及药学上可接受的载体或赋形剂。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010278528.0A CN111317820B (zh) | 2020-04-10 | 2020-04-10 | 剪接因子prpf31抑制剂用于制备药物的用途 |
CN202010278528.0 | 2020-04-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021203798A1 true WO2021203798A1 (zh) | 2021-10-14 |
Family
ID=71166433
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/073519 WO2021203798A1 (zh) | 2020-04-10 | 2021-01-25 | 剪接因子prpf31抑制剂用于制备药物的用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN111317820B (zh) |
WO (1) | WO2021203798A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111317820B (zh) * | 2020-04-10 | 2021-06-11 | 中国药科大学 | 剪接因子prpf31抑制剂用于制备药物的用途 |
CN112691195B (zh) * | 2021-02-02 | 2023-03-14 | 黑龙江省科学院高技术研究院 | Prpf8表达抑制剂在制备治疗肺癌的药物中的应用 |
CN113584038B (zh) * | 2021-09-09 | 2023-11-14 | 深圳雅济科技有限公司 | 一种治疗视网膜疾病的反义寡核苷酸组合及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120197540A1 (en) * | 2011-02-01 | 2012-08-02 | Consiglio Nazionale Delle Ricerche | Markers to predict survival of breast cancer patients and uses thereof |
CN104178556A (zh) * | 2013-05-28 | 2014-12-03 | 北京师范大学 | 神经胶质瘤分子分型基因群及其应用 |
CN108624696A (zh) * | 2018-08-14 | 2018-10-09 | 中国医学科学院北京协和医院 | 分子标记在制备静脉内平滑肌瘤病诊断检测产品中的应用 |
CN111317820A (zh) * | 2020-04-10 | 2020-06-23 | 中国药科大学 | 剪接因子prpf31抑制剂用于制备药物的用途 |
-
2020
- 2020-04-10 CN CN202010278528.0A patent/CN111317820B/zh active Active
-
2021
- 2021-01-25 WO PCT/CN2021/073519 patent/WO2021203798A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120197540A1 (en) * | 2011-02-01 | 2012-08-02 | Consiglio Nazionale Delle Ricerche | Markers to predict survival of breast cancer patients and uses thereof |
CN104178556A (zh) * | 2013-05-28 | 2014-12-03 | 北京师范大学 | 神经胶质瘤分子分型基因群及其应用 |
CN108624696A (zh) * | 2018-08-14 | 2018-10-09 | 中国医学科学院北京协和医院 | 分子标记在制备静脉内平滑肌瘤病诊断检测产品中的应用 |
CN111317820A (zh) * | 2020-04-10 | 2020-06-23 | 中国药科大学 | 剪接因子prpf31抑制剂用于制备药物的用途 |
Non-Patent Citations (2)
Title |
---|
PEEDICAYIL ABRAHAM, VIERKANT ROBERT A., HARTMANN LYNN C., FRIDLEY BROOKE L., FREDERICKSEN ZACHARY S., WHITE KRISTIN L., ELLIOTT EL: "Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes", PLOS ONE, PUBLIC LIBRARY OF SCIENCE, US, vol. 5, no. 1, 27 January 2010 (2010-01-27), US , pages e8884 - 8, XP055856745, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0008884 * |
WEI SONG: "Master’s Thesis", 15 May 2015, PEKING UNION MEDICAL COLLEGE, CN, article WEI SONG: "Study on the association between U2-dependent mRNA splicing complex-related gene polymorphisms and the risk of primary liver cancer", pages: 1 - 62, XP055856749 * |
Also Published As
Publication number | Publication date |
---|---|
CN111317820A (zh) | 2020-06-23 |
CN111317820B (zh) | 2021-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021203798A1 (zh) | 剪接因子prpf31抑制剂用于制备药物的用途 | |
Zhang et al. | MiR-30a regulates the proliferation, migration, and invasion of human osteosarcoma by targeting Runx2 | |
WO2017067454A1 (zh) | Lsd1抑制剂用于防治三阴性乳腺癌的医药用途和药物产品 | |
Dai et al. | MicroRNA‐29b‐3p reduces intestinal ischaemia/reperfusion injury via targeting of TNF receptor‐associated factor 3 | |
CN110592222A (zh) | Triml1作为肝癌的分子标记物的应用 | |
WO2020113877A1 (zh) | E2f6抑制剂的功能与用途 | |
CN108653737B (zh) | Mthfd1l抑制剂在制备舌鳞癌治疗药物中的用途 | |
CN113528528B (zh) | 一种促进耐伊马替尼慢性髓细胞白血病细胞K562/G01凋亡shRNA及其应用 | |
CN113564252B (zh) | 甲基化酶mettl3的新用途 | |
Li et al. | GSG2 promotes tumor growth through regulating cell proliferation in hepatocellular carcinoma | |
CN113230249A (zh) | 土荆皮乙酸在作为或制备Hedgehog信号通路抑制剂中的应用 | |
CN113521080A (zh) | Cx-5461在制备phf6突变的急性髓系白血病的药物中的应用 | |
US11207425B2 (en) | Guide RNA molecule and method for treating cancer | |
CN113521291B (zh) | Znf143-mdig-cdc6轴在肝细胞癌中的应用 | |
CN108295261B (zh) | Phf14的功能与用途 | |
CN112691195B (zh) | Prpf8表达抑制剂在制备治疗肺癌的药物中的应用 | |
CN114767702B (zh) | 一种敲低circXPO1的抑制剂及其在制备治疗胶质瘤药物中的应用 | |
KR20200131290A (ko) | 종양 전이의 약물 치료를 위한 표적 및 이의 응용 | |
CN114703287B (zh) | CXorf56基因在治疗三阴性乳腺癌中的应用 | |
US20150258173A1 (en) | Compositions for modulating invasion ability of a tumor and methods thereof | |
CN116256515A (zh) | Ppdpf在胆管癌诊断及药物制备中的用途 | |
CN117180430A (zh) | Nln神经溶素在制备作为治疗肺癌药物的新用途 | |
CN117089619A (zh) | 一种用于诊断结肠癌的生物标志物及其应用 | |
Li et al. | Influence of GPRC5A-Regulated ABCB1 Expression on Lung Adenocarcinoma Proliferation | |
CN111557943A (zh) | Pd0332991联合奥希替尼在制备治疗nsclc药物中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21784452 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21784452 Country of ref document: EP Kind code of ref document: A1 |