Application of CCDC137 as a target in screening drugs for preventing, alleviating and / or treating hepatocellular carcinoma

Abstract

The present invention provides the use of CCDC137 as a target in the treatment of hepatocellular carcinoma (HCC). Through research, the present invention found that CCDC137 is closely related to the pathological grade and long-term prognosis of HCC. After knocking down CCDC137, HCC proliferation and metastasis are significantly inhibited both in vitro and in vivo. The mechanism is mainly that after knocking down CCDC137, the activation of the β-catenin and AKT pathways is weakened, thereby inhibiting the proliferation, metastasis and stem cell characteristics of HCC cells, and then inhibiting the progression of HCC. Further, the study found that the β-catenin negative regulatory protein LZTS2 is a binding protein of CCDC137. The therapeutic peptide that blocks the binding of CCDC137-LZTS2 inhibits the proliferation of diseased human organs and PDX tumors, and inhibits the progression of HCC in vitro and in vivo.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to application of CCDC137 as a target in preparing a drug for treating hepatocellular carcinoma. Background Art

[0002] Hepatocellular carcinoma (HCC) has a high mortality rate, ranking fourth among cancer-related deaths after lung cancer, breast cancer, and colon cancer, and second among men. Hepatitis B is the most important risk factor for HCC in East Asia, with approximately 60% of HCC cases coexisting with hepatitis B. With improved living conditions, HCC cases caused by alcoholic liver disease and non-alcoholic fatty liver cirrhosis are increasing annually. Systemic therapies, particularly immune checkpoint inhibitors, have significantly improved the long-term prognosis of HCC patients. Atezolizumab combined with bevacizumab and tremelimumab combined with durvalumab are currently the preferred first-line treatments for advanced HCC. Tyrosine kinase inhibitors such as lenvatinib and sorafenib have also significantly prolonged patient survival. However, the lack of commonly treatable molecular mutations in HCC presents challenges in targeted therapy.

[0003] Therefore, it is crucial to deeply explore the potential clinical markers and therapeutic targets of HCC. Summary of the Invention

[0004] The present invention aims to provide the use of CCDC137 as a target in the preparation of drugs for treating hepatocellular carcinoma. Experiments in the present invention have found that knocking down CCDC137 in HCC cells can significantly inhibit HCC tumor stem cell characteristics, proliferation and metastasis in vitro and in vivo, and in HCC tumor xenografts, organoids and PDX models, therapeutic peptides that disrupt CCDC137-LZTS2 binding can inhibit HCC tumor proliferation and metastasis, indicating that CCDC137 inhibitors and substances that block the binding of CCDC137 to LZTS2 have the potential to be used in the preparation of drugs for treating hepatocellular carcinoma.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] In a first aspect of the present invention, there is provided the use of CCDC137 as a target in screening drugs for preventing, alleviating and / or treating hepatocellular carcinoma, wherein the screening method includes screening for substances that can inhibit the expression of the CCDC137 gene or screening for substances that can block the binding of CCDC137 to LZTS2.

[0007] Furthermore, the CCDC137 inhibitor is a drug that inhibits the proliferation and metastasis of HCC xenograft tumors, organoids and PDX models; the CCDC137 inhibitor is a drug that inhibits the progression of HCC tumors.

[0008] In a second aspect of the present invention, there is provided use of a CCDC137 inhibitor in the preparation of a medicament for preventing, alleviating and / or treating hepatocellular carcinoma.

[0009] Furthermore, the CCDC137 inhibitor includes substances that can inhibit CCDC137 gene expression or CCDC137 protein function.

[0010] As a specific embodiment, the CCDC137 inhibitor includes a small molecule inhibitor therapeutic peptide 3, the amino acid sequence of which is shown in SEQ ID NO. 1 (SRVQAGPGSPRRARG).

[0011] In a third aspect of the present invention, provided is the use of a substance that blocks the binding between CCDC137 and LZTS2 in the preparation of a drug for preventing, alleviating and / or treating hepatocellular carcinoma.

[0012] Preferably, the substance that blocks the binding between CCDC137 and LZTS2 includes a small molecule or polypeptide that can block the binding between CCDC137 and LZTS2.

[0013] As a specific embodiment, the substance that blocks the binding between CCDC137 and LZTS2 includes: therapeutic peptide 6 targeting the binding region between CCDC137 and LZTS2, the amino acid sequence of which is shown in SEQ ID NO. 2 (QEIPFRLREIMRSRQ).

[0014] In a fourth aspect of the present invention, a drug for treating hepatocellular carcinoma is provided, wherein the drug for treating hepatocellular carcinoma comprises a CCDC137 inhibitor or a substance that blocks the binding of CCDC137 to LZTS2.

[0015] The drug also includes pharmaceutically acceptable excipients and carriers. The excipients include at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a colorant. The drug can be in the form of at least one of a granule, a tablet, a pill, a capsule, an injection, or a dispersant.

[0016] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0017] The present invention provides the use of CCDC137 as a target in the preparation of a drug for the treatment of liver cancer. Research has shown that knocking down CCDC137 significantly inhibits HCC proliferation and metastasis both in vitro and in vivo. This mechanism is primarily due to reduced activation of the β-catenin and AKT pathways, which inhibits HCC cell proliferation, metastasis, and stem cell properties, thereby inhibiting HCC progression. Furthermore, the study found that LZTS2, a negative regulator of β-catenin, is a binding protein of CCDC137. Therapeutic peptides that block the CCDC137-LZTS2 binding inhibit the proliferation of diseased human organs and PDX tumors, and inhibit HCC progression both in vitro and in vivo. This drug is a potential new drug for the treatment of HCC. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following is a brief introduction to the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0019] Figure 1 To investigate the expression of CCDC137 in HCC and adjacent adjacent tissues and the relationship between CCDC137 and the prognosis of HCC patients. Figure 1 A and B show that CCDC137 is significantly overexpressed in HCC tissue microarray; Figure 1 C: Public database analysis showed that CCDC137 was highly expressed in HCC; Figure 1 D: HCC patients with high expression of CCDC137 have worse long-term prognosis;

[0020] Figure 2 The results show that after CCDC137 knockdown, the proliferation and metastasis of the representative HCC cell line LM9 were significantly inhibited in vitro. Figure 2 A: Knockdown of CCDC137 significantly inhibited the characteristics of HCC cancer stem cells; Figure 2 B: Knockdown of CCDC137 significantly inhibited HCC metastasis; Figure 2 C: Knockdown of CCDC137 significantly inhibited HCC proliferation;

[0021] Figure 3 After CCDC137 was knocked down, the proliferation and metastasis of the representative HCC cell line LM9 were significantly inhibited in vivo; Figure 3 A, 3D: Knockdown of CCDC137 significantly inhibited lung metastasis in MDA-MB-231 mice; Figure 3 B, 3C: Knockdown of CCDC137 significantly inhibited the in vitro invasion ability of MDA-MB-231 cells;

[0022] Figure 4 CCDC137 regulates β-catenin and AKT pathways by binding to LZTS2; Figure 4 A is the candidate CCDC137 binding protein obtained by IP-MS and public data analysis; Figure 4 B: CCDC137 cannot interact with β-catenin; Figure 4 C and 4D show that CCDC137 interacts with LZTS2; Figure 4 E is a Western blotting experiment showing that CCDC137 regulates β-catenin and AKT pathways;

[0023] Figure 5 Therapeutic peptides that block CCDC137-LZTS2 binding upregulate LZTS2 to inhibit β-catenin and AKT pathways; Figure 5 A is the amino acid sequence of the therapeutic peptide; Figure 5 B shows the changes in LZTS2, β-catenin, and AKT pathways in LM9 and Huh7 cells after treatment with therapeutic peptides; Figure 5 C, the optimal working concentration of therapeutic peptides 3 and 6 is 10 μM;

[0024] Figure 6 Therapeutic peptides that block CCDC137-LZTS2 binding inhibit HCC progression in vitro; Figure 6 A: Therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC metastasis; Figure 6 B. Figure 6 C represents the inhibition of HCC proliferation by therapeutic peptide 3 and therapeutic peptide 6; Figure 6 D is the inhibition of HCC tumor stem cell characteristics by single therapeutic peptide 3 and therapeutic peptide 6;

[0025] Figure 7 Therapeutic peptides that block CCDC137-LZTS2 binding inhibit HCC progression in vivo; Figure 7 A is a subcutaneous xenograft tumor model showing that therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC proliferation; Figure 7 B is a liver orthotopic tumor implantation model showing that therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC proliferation and metastasis. Figure 7 C is a lung metastasis model showing that therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC metastasis.

[0026] Figure 8 Therapeutic peptides designed to block CCDC137-LZTS2 binding inhibited the growth of HCC organoids and PDX tumors; Figure 8 A and B show that therapeutic peptide 3 and therapeutic peptide 6 significantly inhibited the growth of HCC organoids; Figure 8 C: Therapeutic peptide 3 and therapeutic peptide 6 significantly inhibited the growth of PDX tumors.

[0027] Figure 9 The mechanism of action of the therapeutic peptide targeting the binding region of CCDC137 and LZTS2. DETAILED DESCRIPTION

[0028] The present invention will be described in detail below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific embodiments and examples are for illustrating the present invention, rather than for limiting the present invention.

[0029] Throughout this specification, unless otherwise specified, the terms used herein should be understood as having the same meaning as commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of any conflict, the present specification shall take precedence.

[0030] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained through existing methods.

[0031] The technical solution of the embodiment of the present application is to solve the above technical problems, and the overall idea is as follows:

[0032] The first part is that knocking down CCDC137 in HCC cells can significantly inhibit HCC tumor stem cell characteristics, proliferation in vitro and in vivo, and metastasis. CCDC137 activates the β-catenin and AKT pathways by regulating LZTS2.

[0033] The second part is that in subcutaneous xenograft tumor models, liver orthotopic implantation models, lung metastasis models and PDX models, therapeutic peptides blocking CCDC137-LZTS2 binding can significantly inhibit the proliferation and metastasis of HCC.

[0034] The following will describe in detail the application of CCDC137 as a target in the preparation of drugs for treating hepatocellular carcinoma in combination with examples and experimental data.

[0035] Example 1: Knockdown of CCDC137 in HCC tumor cells and observation of tumor proliferation and metastasis in vitro and in vivo

[0036] 1. CCDC137 is highly expressed in HCC and is associated with poor prognosis

[0037] Liver cancer clinical sample collection: 42 pairs of liver cancer tissues and adjacent adjacent tissues were provided by Tongji Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology. The entire collection and subsequent experimental procedures adhered to medical ethics and strictly maintained confidentiality of case data. Following surgical removal, tissue samples were quickly cut into small pieces, placed in cryovials, and quickly frozen in liquid nitrogen before being stored at -80°C.

[0038] Immunohistochemistry (IHC) and Statistical Analysis: Immunohistochemistry analysis of the liver cancer microarray was performed using SPSS 13.0 and Graph Pad Prism 6.0. Statistical significance was determined using the standard deviation (±SD) and the Student's t-test. P < 0.05 was considered significant. ***P < 0.001, **P < 0.01, *P < 0.05. The correlation between CCDC137 expression levels and overall survival and recurrence-free survival was analyzed using the online analysis website GEPIA (http: / / gepia.cancer-pku.cn / ) and Kaplan-Meier Plotter (https: / / kmplot.com / analysis / index.php cancer=liver_rnaseq&p=service), respectively. For liver cancer tissue microarray analysis, the Pearson chi-square test of independence was used to determine the correlation between CCDC137 expression in the liver cancer tissue microarray.

[0039] Depend on Figure 1 It can be seen that CCDC137 is highly expressed in HCC and is associated with poor prognosis of HCC;

[0040] We used GEPIA and Kaplan-Meier Plotter online biological databases to analyze the relationship between TDP-43 expression levels and overall survival and recurrence-free survival in patients with liver cancer. The results showed that TDP-43 expression was significantly negatively correlated with overall survival and recurrence-free survival in patients with liver cancer ( Figure 2 At the same time, the analysis results of GEO database GSE36376 showed that the expression level of TDP-43 in liver cancer tissue was significantly higher than that in adjacent tissues ( Figure 2 The above analysis showed that TDP-43 expression was closely related to poor prognosis of liver cancer.

[0041] CCDC137 enhances HCC stem cell characteristics in vitro and promotes HCC proliferation and metastasis

[0042] 1. Vector Construction

[0043] (1) shRNA

[0044] ①CCDC137-shRNA-1:

[0045] 5'-GATGACAACACATACACTTAA-3'(SEQ ID NO.3)

[0046] ②CCDC137-shRNA-2:

[0047] 5'-ACCAGGACGAACAGGAGATTC-3'(SEQ ID NO.4)

[0048] (2) Forward and reverse primers were designed and synthesized according to the shRNA sequence and annealed. The oligonucleotide double strands obtained after annealing were inserted into the pLKO.1 vector (the pLKO.1 vector was linearized by double enzyme digestion with EcoR1 and BamHI endonucleases and then enzyme ligated) to obtain the CCDC137 shRNA knockdown plasmid.

[0049] 2. Knockdown of CCDC137 in vitro inhibits HCC proliferation and metastasis

[0050] (1) To explore the potential role of CCDC137 in the development and progression of liver cancer, we used a plate cloning assay to examine the effect of CCDC137 on the proliferation of liver cancer cells. ShRNA knockdown plasmids, CCDC137-shRNA-1 and CCDC137-shRNA-2, were transiently introduced into the liver cancer cell line LM9 to specifically silence the expression of CCDC137. Data were analyzed using GraphPad 8.0 statistical software. Results are expressed as (mean ± standard deviation), and pairwise comparisons were performed using the rank sum test. P < 0.001 indicated a highly significant difference compared with the control group.

[0051] like Figure 2 A shows that knockdown of CCDC137 significantly inhibits the characteristics of HCC cancer stem cells.

[0052] like Figure 2 C shows that knocking down CCDC137 significantly inhibited the cloning ability of the liver cancer cell line LM9. Conversely, overexpressing CCDC137 specifically in LM9 cells effectively enhanced its cloning ability.

[0053] (2) Transwell assay to detect the effect of CCDC137 on liver cancer cell metastasis

[0054] The results are as follows Figure 2 As shown in B, knockdown of CCDC137 significantly inhibited HCC metastasis.

[0055] In summary, CCDC137 enhances the characteristics of HCC cancer stem cells in vitro and promotes HCC proliferation and metastasis.

[0056] CCDC137 promotes HCC proliferation and metastasis in vivo

[0057] 1. Lentiviral packaging and cell transduction

[0058] The CCDC137 shRNA knockdown plasmid was extracted using the Beijing Zhuangmeng Miniprep Kit. Lentivirus was packaged in HEK293T cells. The specific method is as follows:

[0059] (1) HEK293T cells were plated in a 10 cm culture plate and cultured with DMEM complete medium to ensure that the cells reached 80%-90% confluence at the time of transfection the next day;

[0060] (2) Add 8 μg of the target plasmid, PMD2G, and PSPAx2 in a mass ratio of 4:3:1 to 600 μL Opti-MEM, mix well, add 35 μL PEI transfection reagent, shake again to mix well, and let it stand for 15 minutes;

[0061] (3) Transfection of HEK293T cells: Slowly and evenly drip the plasmid suspension into the HEK293T culture medium. After 6-8 hours, aspirate the culture medium and add 10 mL of fresh DMEM complete medium. Continue culturing for 48 hours after transfection, then collect the cell supernatant. Filter the supernatant through a 0.45 μm filter to obtain the lentiviral solution.

[0062] (4) Lentivirus infection of tumor cells: For infection of cell lines, cells were plated in 6-well plates and cultured for 24 h. After the cells adhered to the wall, the culture medium was aspirated and replaced with lentivirus solution. After 24 h, the culture medium was replaced with fresh culture medium and cultured for another 24 h. Complete culture medium was replaced and puromycin was added for screening. The screening lasted for 1 week before the culture was expanded.

[0063] 2. Construction of nude mouse animal model:

[0064] (1) Construction of subcutaneous xenograft model: culture a sufficient number of cells, digest the cells, count them, and resuspend them in an appropriate amount of serum-free medium; grab the nude mice, and inject 100 μL of cell suspension (containing 1×10 6 cells), ensure that the needle insertion and exit paths are not consistent to avoid cell loss, and regularly record the changes in subcutaneous tumor volume;

[0065] (2) Construction of orthotopic liver implantation model: culture a sufficient number of cells, digest the cells, count them, and resuspend them in an appropriate amount of serum-free culture medium and Matrigel mixture (volume ratio 3:1); anesthetize the nude mice, properly fix them on a warming plate, make a vertical incision in the right upper abdomen to fully expose the left lobe of the liver, and add 50 μL of the prepared cell suspension (containing 8×10 5 cells) were injected into the liver capsule and the incision was sutured;

[0066] (3) Cultivate a sufficient number of cells, digest the cells, count them, and resuspend them in an appropriate amount of serum-free medium; use a mouse tail vein injection instrument to properly fix the nude mice, and inject 200 μL of the prepared cell suspension (containing 2×10 6The cells were injected into the tail vein, and the cotton swab was pressed on the injection site for a few seconds to observe the reaction of the nude mice.

[0067] Depend on Figure 3 It can be seen that knocking down CCDC137 significantly improved the survival of tumor-bearing mice.

[0068] (4) Establishment of a nude mouse tail vein injection liver cancer lung metastasis model

[0069] A total of 15 male BALB / c nude mice (5 weeks old) were used. Each nude mouse was injected with 1 million MDA-MB-231 cells through the tail vein. Two weeks later, they were given control solvent and the above-mentioned stably transfected cell suspension by gavage for 4 weeks. Two weeks after drug withdrawal, in vivo imaging was performed to detect lung metastasis. The mice were then killed, lung tissue was isolated and fixed, and the number and size of lung metastatic nodules were measured.

[0070] Depend on Figure 3 As shown in A and 3D, knockdown of CCDC137 significantly inhibited lung metastasis in MDA-MB-231 mice.

[0071] Transwell assay was used to detect the invasion ability of MDA-MB-231 cells in vitro. Figure 3 As shown in Figures B and 3C, knockdown of CCDC137 significantly inhibited the in vitro invasion ability of MDA-MB-231 cells.

[0072] 4. Pathway Analysis

[0073] IP-MS and public data analysis revealed candidate CCDC137 binding proteins such as Figure 4 As shown in A, Western blot experiments were used to screen and verify the binding proteins of CCDC137. Figure 4 C shows that CCDC137 cannot interact with β-catenin; Figure 4 D shows that CCDC137 interacts with LZTS2.

[0074] LM9 cell line and Huh7 cell line were transformed with empty vector, CCDC137 shRNA1 knockdown plasmid, and CCDC137 shRNA2 knockdown plasmid, respectively, and the expression levels of β-catenin, AKT, and GAPDH were detected by conventional methods.

[0075] Depend on Figure 4 E shows that CCDC137 regulates the β-catenin and AKT pathways by binding to LZTS2.

[0076] Example 2: Investigating the inhibitory effect of CCDC137 inhibitors on tumor growth and metastasis

[0077] 1. Synthesis of therapeutic peptides

[0078] This application designs 6 therapeutic peptides: peptide 1, peptide 2, peptide 3, peptide 4, peptide 5, peptide 6, respectively. Figure 5 As shown in A.

[0079] 2. Therapeutic peptides 3 and 6 block CCDC137-LZTS2 binding

[0080] The above peptides 1 to 6 were added to LM9 and Huh7 cells at a concentration of 10 μM, respectively, and the expression levels of β-catenin, AKT, and GAPDH were detected.

[0081] Depend on Figure 5 B and Figure 5 C shows that therapeutic peptide 3 and therapeutic peptide 6 upregulate LZTS2 and inhibit the activation of β-catenin and AKT pathways; therapeutic peptide 3 and therapeutic peptide 6 inhibit the activation of CCDC137 and LZTS2.

[0082] Therapeutic peptides blocking CCDC137-LZTS2 binding inhibit HCC progression in vitro

[0083] The effect of CCDC137 on the proliferation of liver cancer cells was detected by plate cloning assay. Figure 6 B. Figure 6 C shows that therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC proliferation;

[0084] Transwell assay was used to detect the effect of CCDC137 on the metastasis of liver cancer cells. Figure 6 A shows that therapeutic peptide 3 and therapeutic peptide 6 inhibit HCC metastasis;

[0085] Therapeutic peptides blocking CCDC137-LZTS2 binding inhibit HCC progression and the growth of HCC organoids and PDX tumors in vivo

[0086] 1. Construction of PDX Model

[0087] (1) Collect clean tumor samples from HCC patients during surgery, try to select the part with good activity, vigorous growth, and pink color, rinse the tumor sample with pre-cooled saline and place it in a pre-cooled sample collection tube;

[0088] (2) Purchase several 5-week-old female NOG mice and feed them adaptively for one week;

[0089] (3) Before inoculation of tumor samples, sample activity testing is performed first. Tissue samples must meet the requirement of activity exceeding 50%. Tumor samples are cut into tissue blocks of approximately 2 mm × 2 mm × 2 mm using sterile ophthalmic scissors, washed twice with sample cleaning solution, and placed in pre-cooled sample preservation solution for inoculation;

[0090] (4) Insert the tumor tissue block into the transplant needle, starting from about 2 cm below the armpit of the NOG mouse. Slowly and gently push the transplant needle to the planned inoculation site under the armpit, and slowly push the needle forward. After the tumor tissue block in the transplant needle is pushed into the mouse's armpit, gently remove the needle, continue feeding, and wait for tumor formation. These mice are designated as F0 generation mice.

[0091] (5) After the F0 generation mice have formed tumors, the tumors are removed and the tumors are passaged as described in steps (3) and (4). The passaged mice are recorded as F1 generation mice;

[0092] (6) Purchase 40 5-week-old female NOG mice for use and feed them adaptively for one week;

[0093] (7) Select F1 liver cancer mice with tumors of appropriate size, remove the tumors, cut them into small pieces, and inoculate the tumor tissue into the axilla of 40 NOG mice. Closely monitor the growth and size of the tumors.

[0094] (8) When the average volume of the tumor reaches 100 mm 3 Afterwards, the mice were divided into groups and administered with each drug injected into the tail vein twice a week for 3 consecutive weeks, for a total of 6 times. During the administration period, the mice were weighed and the tumor volume was measured every 3 days, and records were kept.

[0095] 2. Tail Vein Injection and In Vivo Metastasis Monitoring

[0096] Irradiate the mouse with an electric heating lamp for 2-3 minutes until the two veins on the tail vein turn visibly red. Remove the mouse, fix it in a mold, and inject 100 μL (1 μg / μL) of therapeutic peptide solution into the vein (divided into 2 groups, injected with therapeutic peptide 3 solution and therapeutic peptide 6 solution respectively). After stopping bleeding with gauze for 1 minute, put the mouse back into the cage. The drug was administered twice a week, for two weeks in the subcutaneous xenograft model, for three weeks in the orthotopic liver implant model, for four weeks in the lung metastasis model, and for three weeks in the PDX model. The mice were weighed regularly, and the metastasis of tumor cells in the mice was detected using a small animal in vivo imaging device.

[0097] Depend on Figure 7 It can be seen that therapeutic peptides 3 and 6 that block CCDC137-LZTS2 binding inhibit HCC progression in vivo;

[0098] Depend on Figure 8 It can be seen that therapeutic peptides 3 and 6 that block CCDC137-LZTS2 binding inhibit the growth of HCC organoids and PDX tumors.

[0099] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements, but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0100] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0101] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. Use of a substance that blocks the binding of CCDC137 to LZTS2 in the preparation of a drug for preventing, alleviating and / or treating hepatocellular carcinoma, characterized in that: The substance that blocks the binding of CCDC137 to LZTS2 includes: therapeutic peptide 3 or therapeutic peptide 6 targeting the binding region of CCDC137 to LZTS2, the amino acid sequence of the therapeutic peptide 3 is shown in SEQ ID NO.1, and the amino acid sequence of the therapeutic peptide 6 is shown in SEQ ID NO.

2.

2. A drug for treating hepatocellular carcinoma, characterized in that: The drug includes the therapeutic peptide 3 whose amino acid sequence is shown as SEQ ID NO.1 or the therapeutic peptide 6 whose amino acid sequence is shown as SEQ ID NO.2.

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