CN112176064A - Application of ATXN7L3 in diagnosis, treatment and prognosis of liver cancer - Google Patents
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of ATXN7L3 in diagnosis, treatment and prognosis of liver cancer. The invention provides a molecular marker ATXN7L3 related to the occurrence and development of liver cancer, a liver cancer diagnosis product and means, and whether a patient has the risk of liver cancer is judged by detecting the expression level of the molecular marker. Also provides a drug combination or a method for treating liver cancer, which treats liver cancer through specific up-regulation molecular markers. Experiments show that the expression of ATXN7L3 is compared in cancer tissues and para-cancer tissues of HCC clinical patients, and ATXN7L3 is found to be remarkably low expressed in the HCC tissues of the cancer tissues. In addition, the expression of ATXN7L3 is positively correlated with the differentiation degree of HCC tissues, namely, the expression level of ATXN7L3 is higher in HCC tissues with high differentiation degree. And the expression of ATXN7L3 is in negative correlation with the prognosis of patients, namely, the patients with low expression of ATXN7L3 have low overall survival rate and short survival period. In addition, the ATXN7L3 finds that the reduction of the expression of the ATXN7L3 protein can promote the proliferative capacity of HCC cells through in vivo and in vitro functional experiments.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of ATXN7L3 in diagnosis, treatment and prognosis of liver cancer.
Background
Liver cancer is a tumor disease with the highest fatality rate in cancer worldwide, and is generally divided into primary liver cancer and secondary liver cancer, wherein the primary liver cancer can be further divided into cholangiocarcinoma, hepatocellular carcinoma (HCC) and mixed liver cancer. Of the three, HCC is the most common histological subtype in primary liver cancer, and has the characteristics of high recurrence, high metastasis and poor prognosis. Notably, the mortality rate of HCC is ranked at the top in all liver tumors. Although drugs including sorafenib are widely used in clinical treatment, their therapeutic effects are still very limited. Therefore, exploring the development of new molecular mechanisms of HCC has very important significance for the treatment of liver cancer.
ATXN7L3 is called Ataxin 7like 3, and is an important aptamer for regulating and controlling ubiquitination modification of intracellular histones. It was first found to be present in the hSAGA complex, necessary to maintain the histone deubiquitinating enzyme activity of this complex. Together, ATXN7L3 and ENY2 and ubiquitin protease USP22 form the active center of the histone deubiquitinating module (DUBm) in hsga complexes and regulate the deubiquitination of intracellular histone H2A/H2B. Further studies found that ATXN7L3 also binds to the ubiquitin protease USP51 or USP27X, constituting a DUBm motif unrelated to hsaa, regulating intracellular histone ubiquitination levels. However, the expression and action mechanism of ATXN7L3 in HCC have not been reported so far.
Disclosure of Invention
In view of the problems of the prior art, the invention aims to provide the application of ATXN7L3 in liver cancer diagnosis, treatment and prognosis. The invention provides a molecular marker ATXN7L3 related to the occurrence and development of liver cancer, a liver cancer diagnosis product and means, and whether a patient has the risk of liver cancer is judged by detecting the expression level of the molecular marker. And provides a pharmaceutical composition or a method for treating liver cancer, which treats liver cancer through specific up-regulation molecular markers. Experiments show that the expression of ATXN7L3 is compared in cancer tissues and para-cancer tissues of HCC clinical patients, and ATXN7L3 is found to be remarkably low expressed in the HCC tissues of the cancer tissues. In addition, the expression of ATXN7L3 is positively correlated with the differentiation degree of HCC tissues, namely, the expression level of ATXN7L3 is higher in HCC tissues with high differentiation degree. Moreover, the expression of ATXN7L3 is negatively correlated with the prognosis of patients, i.e., patients with low expression of ATXN7L3 have low overall survival rate and short survival time. In addition, the ATXN7L3 finds that the reduction of the expression of the ATXN7L3 protein can promote the proliferative capacity of HCC cells through in vivo and in vitro functional experiments.
In order to achieve the above object, the present invention adopts the following technical solutions.
Application of a reagent for detecting ATXN7L3 expression in preparation of products for diagnosing and/or prognosis judging liver cancer.
Further, the agent is selected from: a probe that specifically recognizes ATXN7L 3; or a primer that specifically amplifies ATXN7L 3.
Further, the product comprises a reagent for detecting the expression level of ATXN7L3 in a sample by a sequencing technology, a nucleic acid hybridization technology, a nucleic acid amplification technology, and the product comprises but is not limited to a reagent, a kit, a chip, a test paper, and a high-throughput sequencing platform.
Application of ATXN7L3 agonist in preparing medicine and pharmaceutical composition for preventing or treating liver cancer.
Further, the pharmaceutical composition comprises an ATXN7L3 agonist.
Further, the agonist is selected from the group consisting of: an interfering molecule that targets ATXN7L3 or its transcription and is capable of promoting expression or transcription of ATXN7L3, comprising: shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid, or a construct capable of expressing or forming said shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid.
Furthermore, the pharmaceutical composition also comprises other medicines compatible with the ATXN7L3 agonist and pharmaceutically acceptable carriers and/or auxiliary materials.
Further, the ATXN7L3 agonist is in any pharmaceutically therapeutically acceptable dosage form.
Further, the ATXN7L3 agonist is in any pharmaceutically therapeutically acceptable dose.
Application of ATXN7L3 in screening potential substances for preventing or treating liver cancer.
The agonists of the invention may be used by formulating pharmaceutical compositions by any means known in the art. Such compositions comprise the active ingredient in admixture with one or more pharmaceutically acceptable carriers, diluents, fillers, binders and other excipients, depending on the mode of administration and the dosage form envisaged. Therapeutically inert inorganic or organic carriers known to those skilled in the art include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, water, sucrose, ethanol, glycerol, and the like, various preservatives, lubricants, dispersants, flavoring agents. Moisturizers, antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like may also be added as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouthfeel or odor upon oral administration, formulations which may be used in such compositions may be in the form of their original compounds as such, or optionally in the form of their pharmaceutically acceptable salts, and the agonists of the invention may be administered alone, or in various combinations, as well as in combination with other therapeutic agents. The compositions so formulated may be administered in any suitable manner known to those skilled in the art for administration of inhibitors or activators as desired. In using the pharmaceutical compositions, a safe and effective amount of an inhibitor of the present invention is administered to a human, wherein the safe and effective amount is typically at least about 100 micrograms per kilogram of body weight for oral administration. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The medicine of the present invention may be prepared into various preparation forms. Including, but not limited to, tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for transdermal, mucosal, nasal, buccal, sublingual or oral use.
The route of administration of the drug of the present invention is not limited as long as it exerts the desired therapeutic effect or prophylactic effect, and includes, but is not limited to, intravenous, intraperitoneal, intraarterial, oral, intramuscular, subcutaneous. In some cases, the administration may be systemic. In some cases topical administration.
The dose of the drug of the present invention is not limited as long as the desired therapeutic effect or prophylactic effect is obtained, and can be appropriately determined depending on the symptoms, sex, age, and the like. The dose of the therapeutic agent or prophylactic agent of the present invention can be determined using, for example, the therapeutic effect or prophylactic effect on a disease as an index.
Compared with the prior art, the invention has the following beneficial effects.
The invention discovers that ATXN7L3 has the function of inhibiting the proliferation of tumor cells in HCC for the first time. ATXN7L3 was low expressed in HCC tumor tissues, and its low expression was negatively correlated with patient prognosis. The detection of the expression condition of ATXN7L3 in HCC patient tissues is likely to be helpful for diagnosis and prognosis judgment, the preparation of an ATXN7L3 expression vector or the induction of the expression of the ATXN7L3 expression vector can achieve the functions of treating HCC and relieving HCC progress, and the combination with the existing treatment scheme can achieve better treatment effect.
Drawings
Figure 1 is the expression of ATXN7L3 in HCC tumor tissue and corresponding paraneoplastic tissue. Wherein T is HCC tumor tissue, and N is para-cancer tissue.
Figure 2 is the expression of ATXN7L3 in HCC tumor tissues of different degrees of differentiation.
Figure 3 is the expression of ATXN7L3 in HCC tumor tissues of different degrees of differentiation.
Figure 4 is the inhibition of growth proliferation of HCC cells in vitro by ATXN7L3 in vivo.
FIG. 5 is a map of the ATXN7L3 expression plasmid.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are only preferred embodiments of the present invention and are not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art without departing from the spirit and the principle of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Examples are given.
Firstly, preparation of an expression sequence.
The mRNA sequence of ATXN7L3 is shown as SEQ ID NO.2, the amino acid sequence of ATXN7L3 is shown as SEQ ID NO.1, expression plasmids of the ATXN7L3 are prepared, and the plasmid map is shown as FIG. 5.
Second, the application of ATXN7L3 in diagnosis, treatment and prognosis of liver cancer.
As shown in fig. 1, expression of ATXN7L3 in HCC tumor tissue and corresponding paraneoplastic tissue. Matched samples of tumor tissues and corresponding paraneoplastic tissues from 28 clinical HCC patients were collected, Western Blot was used to detect the expression level of ATXN7L3 in them (fig. 4A), GAPDH was used as an internal reference, and the results were quantitatively analyzed (fig. 4B). The results showed that in 21 of the samples, ATXN7L3 was significantly less expressed in HCC tumor tissue than in the corresponding paraneoplastic tissue.
As shown in Table 1, the relationship between the expression of ATXN7L3 in HCC tissues and the clinical pathological parameters of patients is higher, and the expression of ATXN7L3 is higher in the tissues with high differentiation degree. Paraffin sections of HCC tumor tissues from 64 clinical patients were immunohistochemically stained to detect the expression level of ATXN7L 3. The expression of ATXN7L3 was scored according to the degree of staining and analyzed for its relationship with the age, sex, degree of pathological tissue differentiation and alpha-fetoprotein (AFP) expression of the patient. The results show that the expression of ATXN7L3 has no correlation with the age, sex and AFP expression of patients, but is related with the differentiation degree of HCC pathological tissues (P < 0.005).
Table 1.
Relation between the clinicopathologic variables and ATXN7L3 expression in HCC
a：Chi-square test
b：Mean age
As shown in fig. 2, representative photographs of ATXN7L3 expression in HCC tissues of different degrees of differentiation. ATXN7L3 was immunohistochemically stained in paraffin sections of HCC tumor tissue, with higher expression in HCC tissue at high differentiation level (Well), higher expression in HCC tissue at medium differentiation level (Moderate), and low expression in HCC tissue at low differentiation level (port).
As shown in FIG. 3, the expression of ATXN7L3 is negatively correlated with the clinical prognosis of HCC patients, and patients with low ATX expression have low overall survival rate and short survival time. The paraffin sections of 85 cases of HCC tumor tissues bearing patient prognosis information from ATXN7L3 were immunohistochemically stained and scored for staining intensity. Thereafter, cases were divided into two low-and high-expression groups of ATXN7L3 according to median, and the overall survival rate and survival time of the two groups of patients were analyzed. The results show that patients with high expression of ATXN7L3 have high overall survival rates and long survival times.
As shown in fig. 4, ATXN7L3 inhibited growth and proliferation of HCC cells at the cellular level and in nude mice. ATXN7L3 inhibited growth and proliferation of HCC cells at the cellular level and in nude mice. After transfection of ATXN7L3 expression plasmid or control plasmid in HCC cell line HCCLM3, MTS experiment was performed to detect cell growth, and it was found that over-expression of ATXN7L3 can inhibit growth and proliferation of HCC cells, as shown in FIG. 4A; after the cells were infected with viruses that knock down ATXN7L3 or control viruses, cell counting was performed and growth curves were drawn, and it was found that the knock down of ATXN7L3 expression can promote growth and proliferation of the cells, as shown in fig. 4B; after the cells are infected with viruses or control viruses for knocking down ATXN7L3, plating and culturing, after the cells are obviously cloned, fixing and staining are carried out, and it is found that the knocking down of the expression of ATXN7L3 can promote the clonogenic capacity of the cells, as shown in FIG. 4C; after the cells were infected with the virus for knocking down ATXN7L3 or the control virus, the cells were inoculated to the axilla of nude mice, the outer diameter of the formed tumor was measured every other day, and after 2 weeks of dissection and weighing, it was found that in nude mice, the knocking down of ATXN7L3 expression promoted the growth and proliferation of HCCLM3 cells, and the tumor formed by the cells with the knocked down of ATXN7L3 expression was small in volume, as shown in fig. 4D and 4E; the growth rate is fast as shown in FIG. 4F; and the tumor weight is greater as shown in fig. 4G.
Sequence listing
<110> university of Chinese medical science
Application of <120> ATXN7L3 in diagnosis, treatment and prognosis of liver cancer
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 354
<212> PRT
<213> Artificial sequence
<400> 1
mkmeemslsg ldnskleaia qeiyadlved sclgfcfevh ravkcgyffl ddtdpdsmkd 60
feivdqpgld ifgqvfnqwk skecvcpncs rsiaasrfap hlekclgmgr nssrianrri 120
ansnnmnkse sdqednddin dndwsygsek kakkrksdkl wylpfqnpns prrskslkhk 180
ngelsnsdpf kynnstgisy etlgpeelrs llttqcgvis ehtkkmctrs lrcpqhtdeq 240
rrtvriyflg psavlpeves sldndsfdmt dsqalisrlq wdgssdlsps dsgssktsen 300
qgwglgtnss esrktkkkks hlslvgtasg lgsnkkkkpk ppapptpsiy ddin 354
<210> 2
<211> 1065
<212> DNA
<213> Artificial sequence
<400> 2
ATGAAAATGG AGGAAATGTC TTTGTCTGGC CTGGATAACA GCAAACTAGA GGCCATCGCT 60
CAGGAGATAT ACGCGGACCT GGTCGAGGAT TCTTGTTTGG GATTCTGCTT TGAGGTACAC 120
CGGGCTGTCA AGTGTGGCTA CTTCTTCTTG GACGACACGG ACCCTGATAG CATGAAGGAT 180
TTTGAGATCG TGGACCAGCC GGGCTTGGAC ATCTTTGGAC AGGTTTTCAA CCAGTGGAAG 240
AGCAAGGAGT GTGTTTGCCC CAATTGCAGT CGCAGCATTG CCGCCTCCCG CTTTGCTCCC 300
CATCTGGAGA AGTGCCTGGG AATGGGTCGG AACAGCAGCC GAATCGCCAA CCGCCGGATT 360
GCCAATAGCA ACAATATGAA TAAGTCTGAG AGTGACCAAG AAGATAATGA TGACATCAAT 420
GACAACGACT GGTCCTATGG CTCGGAGAAG AAAGCCAAGA AGAGAAAGTC AGACAAGCTA 480
TGGTATCTCC CATTCCAGAA CCCCAATTCC CCTCGAAGAT CCAAGTCATT AAAACACAAA 540
AATGGGGAAC TTAGCAATTC GGATCCTTTT AAGTATAACA ATTCAACTGG GATCAGCTAT 600
GAGACCCTGG GGCCGGAGGA GCTTCGCAGC CTGCTAACCA CGCAATGTGG GGTGATTTCT 660
GAACACACCA AGAAGATGTG CACAAGGTCC CTGCGCTGCC CACAGCACAC AGATGAGCAG 720
AGGCGAACCG TACGGATTTA TTTTCTCGGG CCCTCGGCTG TCCTTCCAGA GGTCGAGAGC 780
TCCCTGGATA ATGACAGCTT TGACATGACT GACAGCCAGG CCCTGATCAG CCGGCTTCAG 840
TGGGACGGCT CCTCTGACCT CTCACCCTCT GATTCAGGCT CCTCCAAGAC GAGTGAAAAT 900
CAGGGATGGG GTCTAGGTAC CAACAGCTCT GAGTCACGGA AAACCAAGAA AAAGAAATCC 960
CATCTGAGCC TGGTAGGGAC TGCCTCCGGC CTAGGTTCCA ACAAGAAGAA GAAGCCAAAG 1020
CCACCGGCAC CCCCGACGCC CAGCATCTAT GATGACATCA ACTGA 1065
Claims (10)
1. Application of a reagent for detecting ATXN7L3 expression in preparation of products for diagnosing and/or prognosis judging liver cancer.
2. The use of claim 1, wherein the agent is selected from the group consisting of: a probe that specifically recognizes ATXN7L 3; or a primer that specifically amplifies ATXN7L 3.
3. The use of claim 1, wherein the product comprises a reagent for detecting the expression level of ATXN7L3 in the sample by sequencing technology, nucleic acid hybridization technology, nucleic acid amplification technology, and the product comprises but is not limited to reagents, kits, chips, test strips, high throughput sequencing platforms.
Application of ATXN7L3 agonist in preparing medicine and medicine composition for preventing and treating liver cancer.
5. The use of claim 3, wherein the pharmaceutical composition comprises an ATXN7L3 agonist.
6. The use of claim 3, wherein the agonist is selected from the group consisting of: an interfering molecule that targets ATXN7L3 or its transcription and is capable of promoting expression or transcription of ATXN7L3, comprising: shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid, or a construct capable of expressing or forming said shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid.
7. The use of claim 3, wherein the pharmaceutical composition further comprises other drugs compatible with the agonist and a pharmaceutically acceptable carrier and/or adjuvant.
8. The use of claim 3 wherein the ATXN7L3 agonist is in any pharmaceutically acceptable dosage form.
9. The use of claim 3 wherein the ATXN7L3 agonist is at any pharmacotherapeutically acceptable dose.
Application of ATXN7L3 in screening potential substances for preventing or treating liver cancer.
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| CN111417730A (en) * | 2017-11-20 | 2020-07-14 | 托雷莫治疗股份公司 | Diagnostic method |
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| CN111417730A (en) * | 2017-11-20 | 2020-07-14 | 托雷莫治疗股份公司 | Diagnostic method |
Non-Patent Citations (4)
| Title |
|---|
| DAN-DAN XIONG等: "High throughput circRNA sequencing analysis reveals novel insights into the mechanism of nitidine chloride against hepatocellular carcinoma", 《CELL DEATH AND DISEASE》 * |
| GAO-MIN LIU等: "Key genes associated with diabetes mellitus and hepatocellular carcinoma", 《PATHOLOGY - RESEARCH AND PRACTICE》 * |
| JOE BEAN等: "Hepatocellular carcinoma reduces ATXN7L3 to evade estrogen-dependent growth suppression", 《EBIOMEDICINE》 * |
| NING SUN等: "ATXN7L3 positively regulates SMAD7 transcription in hepatocellular carcinoma with growth inhibitory function", 《EBIOMEDICINE》 * |
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