CN117582506B - Application of transmembrane protein TMEFF1 inhibitor in preparation of medicine for treating neuroblastoma - Google Patents
Application of transmembrane protein TMEFF1 inhibitor in preparation of medicine for treating neuroblastoma Download PDFInfo
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the field of medicines, and particularly relates to application of a transmembrane protein TMEFF1 inhibitor in preparation of a medicine for treating neuroblastoma. The research shows that the transmembrane protein TMEFF1 is low-expressed in normal cells such AS MCF10A, hTERT RPE-1 and the like, and is remarkably high-expressed in NB cell lines such AS SK-N-SH, SK-N-AS, SK-N-BE (2), IMR32 and the like. Further studies have found that knocking down TMEFF1 significantly inhibits NB cell proliferation, but knocking down TMEFF1 does not affect normal cell line proliferation. The results show that the transmembrane protein TMEFF1 promotes NB proliferation and tumorigenesis and has potential to be used as a novel NB tumor antigen and a novel NB tumor immunotherapy target.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a transmembrane protein TMEFF1 inhibitor in preparation of a medicine for treating neuroblastoma.
Background
Neuroblastoma (NB) originates from the sympathetic nervous system dysplastic neural crest, is the most common extracranial solid tumor in children, and has a morbidity of about 10.2 cases/100 tens of thousands/15 years old and accounts for about 15% of all childhood cancer deaths. Although clinical accurate treatment means of NB are gradually perfected in recent years, and the application of multidisciplinary combined diagnosis and treatment modes such as high-dose chemotherapy, surgical excision, targeted treatment and the like is gradually mature, about 50% of high-risk NB infants still develop progress or relapse in treatment, the survival rate of 5 years is still loitering at 30-40%, and the long-term prognosis is extremely poor. Therefore, the existing treatment method and system are difficult to meet the accurate treatment requirement, and clinical diagnosis and treatment of the NB infant face a great challenge. Therefore, establishing more accurate targeted diagnostic and therapeutic strategies to improve NB outcome outcomes with poor prognosis is a great challenge and research hotspot for current NB clinical diagnosis and treatment. However, research on NB precise molecular characteristics is currently limited to a few important oncogenes, such as MYCN, ALK and other important oncogenes, but MYCN lacks targeting drugs until now, and ALK has a small mutation ratio in NB, so that it is difficult to meet the treatment requirements of NB precise, efficient and widely used.
Drugs targeting Neuroblastoma (NB) that are currently marketed have only anti-GD 2 antibodies, such as Dinutuximab, approved by the FDA in the united states and incorporated into the first line therapy of NB, but have severe pain, fever, low platelet count, etc. side effects. Thus, the discovery of molecules specifically expressed in NB cells, and the development of targeted therapeutic drugs against such molecules, is a new idea for the treatment of NB. Studies have shown that NB has multiple potential therapeutic targets, such as histone modification enzyme EZH2 to promote NB cell proliferation, and that EZH2 inhibitors, in combination with other drugs, can inhibit NB growth at in vitro levels; ALK has mutation in part of NB tumor, ALK inhibitor crizotinib, lorlatinib can target ALK mutant to inhibit NB development; inhibitors Nutlins, SAR405838 (MI-77301), RG7388 (RO 5503781 or idasan) targeting MDM2 can inhibit p53-MDM2 interactions in NB and activate p 53-induced apoptosis signals; aurora kinase (AURKA) inhibitor MLN8237 (aliert ib) was able to inhibit NB growth in xenograft mouse models by promoting MYCN degradation. However, the above target molecules are all located in the cell membrane and cannot be subjected to therapeutic intervention by looking at the way of antibody therapy. In recent years, research has found that transmembrane protein GPC2 is a novel potential NB cell surface target molecule, but targeted GPC2 therapy still lacks safety and efficacy-related clinical evidence.
Based on the above, the technical scheme of the invention is also provided.
Disclosure of Invention
In order to solve the problems in the prior art, the scheme of the invention is to provide an application of a transmembrane protein TMEFF1 inhibitor in preparing a medicament for treating neuroblastoma.
TMEFF1 (Transmembrane protein with EGF like and two follistatin like domains 1) is a single transmembrane protein, and the extracellular domain comprises an epidermal growth factor-like domain and two follistatin-like domains.
Preferably, the agent is an agent that reduces proliferation and/or clonogenic formation of neuroblastoma.
Preferably, the agent is an agent that reduces the relative levels of the mRNA of TMEFF1, which mRNA sequence is:
5’- CACATGCCTTGCCCTGAAA-3’（SEQ ID NO.1）。
preferably, the agent is an agent that reduces the relative levels of the mRNA of TMEFF1, which mRNA sequence is:
5’- TGTGGACCCTGCAAATATA-3’（SEQ ID NO.2）。
preferably, the agent is an agent that reduces the relative levels of the mRNA of TMEFF1, which mRNA sequence is:
5’- TGTACAGATTGCCATCATA-3’（SEQ ID NO.3）。
preferably, the medicine is a preparation prepared by taking a transmembrane protein TMEFF1 inhibitor as a raw material and adding medical acceptable auxiliary materials.
Preferably, the formulation is an oral formulation, an injectable formulation or an inhaled formulation.
Preferably, the oral preparation is any one of tablets, capsules, granules, pills, powder and oral solution.
The beneficial effects of the invention are as follows:
the research shows that the transmembrane protein TMEFF1 is low-expressed in normal cells such AS MCF10A, hTERT RPE-1 and the like, and is remarkably high-expressed in NB cell lines such AS SK-N-SH, SK-N-AS, SK-N-BE (2), IMR32 and the like. Further studies have found that knocking down TMEFF1 significantly inhibits NB cell proliferation, but knocking down TMEFF1 does not affect normal cell line proliferation. The results show that the transmembrane protein TMEFF1 promotes NB proliferation and tumorigenesis and has potential to be used as a novel NB tumor antigen and a novel NB tumor immunotherapy target.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the relative levels of mRNA in different cell types for TMEFF1 of example 1.
FIG. 2 is a chart showing the proliferation and crystal violet staining of NB cells in the control SiCtrl in example 2.
FIG. 3 is a crystal violet staining chart of NB cell proliferation in experimental group siTMEFF1-1# in example 2.
FIG. 4 is a crystal violet staining chart of NB cell proliferation in experimental group siTMEFF1-2# in example 2.
FIG. 5 is a crystal violet staining chart of NB cell proliferation in experimental group siTMEFF1-3# in example 2.
Fig. 6 is a graph of relative cell area data for each group in example 2 (representing a significant difference in p <0.01 compared to the control siCtrl group).
Fig. 7 is a graph of mRNA versus level data for each group of TMEFF1 in example 2 (indicating that p <0.01, with significant differences compared to the control siCtrl group).
Fig. 8 is a graph of mRNA versus level data for each group of TMEFF1 in example 3 (indicating that p <0.01 has significant differences compared to the control group shCtrl group).
Fig. 9 is a graph of relative cell growth rate data for each group in example 3 (representing a significant difference in p <0.01 compared to the control group shCtrl group).
FIG. 10 is a crystal violet staining chart of NB cell clones in control shCtrl in example 3.
FIG. 11 is a crystal violet staining chart of NB cell clones in experimental group shTMEFF1-1# in example 3.
FIG. 12 is a crystal violet staining chart of NB cell clones in experimental group shTMEFF1-2# in example 3.
Fig. 13 is a graph of NB cell clone data for each group in example 3 (representing a significant difference in p <0.01 compared to the control group shCtrl group).
FIG. 14 is a chart showing the crystal violet staining of normal cell proliferation in the control SiCtrl in example 4.
FIG. 15 is a crystal violet staining chart of normal cell proliferation in experimental group SiTMEFF1-2# in example 4.
FIG. 16 is a crystal violet staining chart of normal cell proliferation in experimental group SiTMEFF1-3# in example 4.
FIG. 17 is a graph showing the relative cell area data of each group in example 4.
Fig. 18 is a graph of mRNA versus level data for each group of TMEFF1 in example 4 (indicating that p <0.01, with significant differences compared to the control siCtrl group).
FIG. 19 is a chart showing the crystal violet staining of normal cell proliferation in the control SiCtrl in example 5.
FIG. 20 is a crystal violet staining pattern of normal cell proliferation in experimental group SiTMEFF1-2# in example 5.
FIG. 21 is a crystal violet staining chart of normal cell proliferation in experimental group SiTMEFF1-3# in example 5.
FIG. 22 is a graph of relative cell area data for each group in example 5.
Fig. 23 is a graph of mRNA versus level data for each group of TMEFF1 in example 5 (indicating that p <0.01, with significant differences compared to the control siCtrl group).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, based on the examples herein, which are within the scope of the invention as defined by the claims, will be within the scope of the invention as defined by the claims.
Example 1
4 NB cell lines (SK-N-SH, SK-N-AS, SK-N-BE (2), IMR 32) and 2 normal cell lines (MCF 10A, hTERT RPE-1) were selected, and the RNA levels of TMEFF1 were examined, respectively. The results are shown in fig. 1, which shows: TMEFF1 is highly expressed in NB cell lines, but not in normal cell lines.
The tumor cell types used in this example were neuroblastoma cell lines, and the normal cell lines were human retinal pigment epithelial cell HTERT RPE-1 and human normal mammary epithelial cell MCF10A.
Example 2
In NB cell line SK-N-BE (2), three siRNA sequences of different sequences (designated as siTMEFF1-1#, siTMEFF1-2#, siTMEFF1-3#, respectively) were used. Wherein: the target sequences are respectively:
siTMEFF1-1#：5’- CACATGCCTTGCCCTGAAA-3’（SEQ ID NO.1），
siTMEFF1-2#：5’- TGTGGACCCTGCAAATATA-3’（SEQ ID NO.2），
siTMEFF1-3#：5’- TGTACAGATTGCCATCATA-3’（SEQ ID NO.3）。
the TMEFF1 is knocked down instantaneously and the proliferation of NB cells is detected, the experimental group is the siTMEFF1-1#, the siTMEFF1-2# and the siTMEFF1-3#, and the control group is the siCtrl (not knocked down). The results are shown in fig. 2 to 7, which show: the TMEFF1 knockdown resulted in a significant decrease in proliferation capacity of NB cells.
Example 3
NB cells (SK-N-BE (2)) with stable knockdown of TMEFF1 were constructed, the experimental groups were shTMEFF1-1# (the target sequence was identical to siTMEFF 1-1#) and shTMEFF1-2# (the target sequence was identical to siTMEFF 1-2#), and the control group was shCtrl (no knockdown of TMEFF 1). The cell proliferation curve was detected using a real-time cell detector. The clonogenic capacity of the cells was observed using a clonogenic assay. The results are shown in fig. 8 to 13, which show: stable knockdown of TMEFF1 resulted in a significant decrease in proliferation and clonogenic capacity of NB cells.
In addition, for ease of understanding, it is emphasized again that the "stable knockdown" approach is adopted in this embodiment, while the "instantaneous knockdown" approach is adopted in embodiment 2.
Example 4
In the normal cell line MCF10A, siRNA of two different sequences (SiTMEFF1-2#, siTMEFF1-3#) were used, the target sequence was as in example 2. The experimental groups are sitmafff 1-2# and sitmafff 1-3#, and the control group is sittrl (not knocked down). Knocking down TMEFF1 and detecting proliferation of cells, the results are shown in FIG. 14-FIG. 18, which show that: TMEFF1 knockdown had no significant effect on the proliferative capacity of normal cells MCF10A.
Example 5
In the normal cell line hTERT RPE-1, two siRNAs of different sequences (siTMEFF1-2#, siTMEFF1-3#) were used, and the target sequence was the same as in example 2. The experimental groups are sitmafff 1-2# and sitmafff 1-3#, and the control group is sittrl (not knocked down). The TMEFF1 was knocked down and the proliferation of cells was examined, and the results are shown in FIGS. 19 to 23, which show that: TMEFF1 knockdown has no significant effect on the proliferative capacity of normal cells hTERT RPE-1.
Total conclusion
(1) The transmembrane protein TMEFF1 is specifically highly expressed in NB cells, but is very poorly expressed in normal cells.
(2) In NB cells, knockdown of TMEFF1 reduced proliferation and clonogenic capacity of NB cells.
(3) In normal cells, knocking down TMEFF1 does not affect proliferation of normal cells.
(4) Transmembrane protein TMEFF1 promotes the malignant proliferation of NB cells, is a novel driving gene for the malignant proliferation of NB cells, and is very important for further developing a targeting antibody or a targeting CAR-T cell because TMEFF1 is a membrane localization protein, which suggests that TMEFF1 can become a novel immunotherapeutic target of NB.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (4)
1. Use of a transmembrane protein TMEFF1 inhibitor in the manufacture of a medicament for attenuating neuroblastoma proliferation and/or clone formation, wherein the transmembrane protein TMEFF1 inhibitor is an siRNA for reducing the relative mRNA level of TMEFF1, the siRNA having a corresponding mRNA sequence of:
5’- CACATGCCTTGCCCTGAAA-3’；
and/or 5'-TGTGGACCCTGCAAATATA-3';
and/or 5'-TGTACAGATTGCCATCATA-3'.
2. The use according to claim 1, wherein the medicament is a preparation prepared by adding pharmaceutically acceptable auxiliary materials to a transmembrane protein TMEFF1 inhibitor as a raw material.
3. The use according to claim 2, wherein the formulation is an oral formulation, an injectable formulation or an inhalable formulation.
4. The use according to claim 3, wherein the oral formulation is any one of a tablet, a capsule, a granule, a pill, a powder, an oral solution.
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