Application of polypeptide and derivative thereof in prevention and treatment of tumors

Abstract

The invention belongs to the technical field of biology, and relates to a polypeptide or a derivative thereof and an application of the polypeptide or the derivative in preparation of an anti-tumor drug. In particular discloses a polypeptide targeting SRC and TRIB3 or a derivative of the polypeptide and application of the polypeptide in preparation of a medicine for treating tumors. The amino acid sequence table of the polypeptide is as shown in SEQ ID No. 1 and SEQ ID No. 2. The polypeptide or the polypeptide derivative can be specifically combined with TRIB3, so that TRIB3 / SRC interaction is blocked, SRC and TRIB3 protein degradation is promoted, and therefore, the polypeptide or the polypeptide derivative can be applied to preparation of drugs for treating and preventing pancreatic cancer cells, liver cancer cells and kidney cancer cells. The prepared medicine has the advantages of being remarkable in curative effect, small in toxic and side effect and safe to use when being used for treating tumor diseases.

Description

Technical Field

[0001] The invention belongs to the field of biotechnology, and specifically relates to a polypeptide or a derivative thereof and application thereof in preparing medicines for treating and preventing tumors. Background Art

[0002] Tumor stem cells are the source of tumor occurrence and a key factor in tumor recurrence, metastasis and drug resistance. At present, the main treatment strategies for tumors are surgery and chemotherapy. Although great success has been achieved, the drug resistance, recurrence and metastasis generated during the treatment process have led to a serious reduction in patient survival. Therefore, targeting tumor stem cells is an important idea to solve the above problems. The tumor microenvironment is the soil for maintaining tumor stem cells. The tumor microenvironment can stimulate tumor cells to highly express the stress protein TRIB3, TRIB3 / SRC interaction, inhibit SRC protein degradation, and cause SRC accumulation in cells. SRC accumulates in the cell nucleus and plays a role in promoting tumor stemness and tumor metastasis. Therefore, the TRIB3 / SRC interaction plays an important role in maintaining tumor stem cell function and tumor progression. Research on the lead compound targeting this interaction will provide new treatment strategies for tumor recurrence, metastasis and drug resistance.

[0003] Pancreatic cancer is a highly invasive malignant tumor with a very poor prognosis. The five-year survival rate is about 11%, which is the third leading cause of cancer-related death. Radical resection is currently the only possible cure for pancreatic cancer, but due to the insidious onset and high malignancy of pancreatic cancer, most patients have invasion of important blood vessels around the tumor at the time of initial diagnosis, resulting in low surgical success rate and high postoperative recurrence rate. Chemotherapy, radiotherapy and targeted therapy are prone to drug resistance, and immunotherapy is difficult to benefit due to low tumor immunogenicity. Therefore, finding new therapeutic targets is of great significance for the treatment of pancreatic cancer. Primary liver cancer is one of the most common malignant tumors in the world and ranks second in the cause of cancer death in my country. Current treatment methods mainly include drug chemotherapy and surgical treatment, but patients are prone to drug resistance, even multidrug resistance, when receiving chemotherapy. Tumor patients mainly die from tumor recurrence and metastasis. Therefore, reducing the stemness of liver cancer cells and inhibiting their migration and invasion are the key to liver cancer prevention. Kidney cancer is one of the most common malignant tumors of the urinary system worldwide, and its incidence and mortality rates are both on the rise. Renal cancer cells are insensitive to chemotherapy and radiotherapy. Although surgery can improve the prognosis of renal cancer patients, the recurrence rate after surgery is high and the five-year survival rate is low. SRC protein belongs to the SRC family kinase (SFKs) member. It is the most studied protein and the one most closely related to human diseases. Abnormal expression is related to tumors such as liver cancer, pancreatic cancer, and kidney cancer. The tumor microenvironment can stimulate tumor cells to highly express the stress protein TRIB3. TRIB3 / SRC interacts with each other, inhibiting the degradation of the proto-oncoprotein SRC and maintaining the function of pancreatic cancer cells. Therefore, as a key mechanism for the tumor microenvironment to maintain the function of pancreatic cancer cells, TRIB3 / SRC interaction is a potential target for targeting pancreatic cancer cells. By targeting the TRIB3 / SRC interaction and promoting the degradation of SRC and TRIB3 proteins, it will play an important role in the treatment of pancreatic, liver, and kidney tumor recurrence and resistance strategies. TRIB3 protein / protein interaction plays an important role in various biological functions and is also a potential therapeutic target for various human diseases. At present, drugs that block protein / protein interactions are a hot area for new drug research and development. Protein peptides and their analogs can serve as leads for interfering with protein / protein interactions.

[0004] Compounds or peptide drugs targeting the TRIB3 / SRC interaction can promote the degradation of SRC and TRIB3 proteins and inhibit their downstream signaling pathways. They have strong targeting and few side effects, and have good drug development prospects for inhibiting tumor occurrence and development. Summary of the invention

[0005] The technical problem to be solved by the present invention is to address the current situation that SRC and TRIB3 lead to high drug resistance rate and lack of drugs that directly target tumor stem cells. Provided is a polypeptide or its derivatives that reduce the expression of SRC and TRIB3 proteins and their use in the preparation of drugs for treating tumors.

[0006] After in-depth research and repeated experiments, the inventors of the present invention have found that the polypeptides SRC-1-2 and TAT-SRC-1-2 (see the sequence table SEQ ID No. 1 and SEQ ID No. 2 for the amino acid sequence) that can target and reduce the expression of SRC and TRIB3 proteins are obtained, which can inhibit the proliferation of various tumor cells, in vitro spheroidization, and in vivo and in vitro tumor growth, and thus can be used in the preparation of drugs for treating tumors. Based on the inventors' research work, the present invention provides the following technical solutions.

[0007] One of the technical solutions provided by the present invention is: a polypeptide or a derivative thereof, wherein the amino acid sequence of the polypeptide is as shown in the amino acid sequence of SEQ ID No. 1 and SEQ ID No. 2 in the sequence list.

[0008] The poly or its derivatives can reduce the expression of SRC and TRIB3 proteins.

[0009] The polypeptide derivatives are conventional derivatives in the art, preferably, including chimeric peptides formed by connecting the polypeptide and a cell-penetrating peptide, fusion peptides formed by the polypeptide and a virus, and conventional modifications of the polypeptide or its derivatives, including acetylation, amidation, cyclization, glycosylation, phosphorylation, alkylation, biotinylation, fluorescent group modification, polyethylene glycol PEG modification, and immobilization modification.

[0010] The cell-penetrating peptide of the present invention is a conventional cell-penetrating peptide in the art, as long as it can assist in delivering the polypeptide into cells to exert its effect. Generally, the cell-penetrating peptide is a short peptide molecule composed of 10 to 30 amino acids.

[0011] Among them, the amino acid sequences shown in the above SEQ ID No.1 and SEQ ID No.2 can be appropriately replaced, deleted or added, as long as the modified amino acid sequence can still specifically bind to TRIB3 and maintain the activity before the modification.

[0012] The second technical solution provided by the present invention is: the use of a polypeptide or a derivative thereof described in one of the technical solutions of the present invention in the preparation of a drug for treating or preventing diseases related to SRC and TRIB3. And the use of a polypeptide or a derivative thereof described in one of the technical solutions of the present invention in the preparation of a drug for treating and / or preventing tumors.

[0013] The tumor is a conventional tumor in the art. Preferably, it is pancreatic cancer, liver cancer, and kidney cancer. Pancreatic cancer, liver cancer, and kidney cancer. Among them, the pancreatic cancer is pancreatic adenocarcinoma, exocrine gland cancer, ampullary cancer, and endocrine pancreatic tumor; liver cancer is hepatocellular carcinoma; kidney cancer is clear cell and papillary renal cell carcinoma.

[0014] The prevention is conventional prevention in the art, preferably refers to preventing or reducing the occurrence of tumors after use when possible tumor factors exist. The treatment is conventional treatment in the art, preferably refers to reducing the degree of tumors, or curing tumors to normalize them, or slowing down the progression of tumors.

[0015] The third technical solution provided by the present invention is: a pharmaceutical composition, which contains a polypeptide or a derivative thereof as described in one of the technical solutions of the present invention and a biologically or pharmaceutically acceptable carrier or excipient.

[0016] Furthermore, the pharmaceutical composition contains a polypeptide or a derivative thereof as an active ingredient as described in one of the technical solutions of the present invention, or contains other compounds having anti-pancreatic cancer, liver cancer, and kidney cancer activity as active ingredients.

[0017] The active ingredient refers to a compound having the function of preventing or treating tumors. In the pharmaceutical composition, the polypeptide targeting the inhibition of SRC and TRIB3 protein expression or the polypeptide can be used as an active ingredient alone or together with other compounds having anti-tumor activity.

[0018] The administration route of the pharmaceutical composition of the present invention is preferably injection or oral administration. The injection preferably includes intravenous injection, intramuscular injection, intraperitoneal injection, intradermal injection or subcutaneous injection. The pharmaceutical composition is in various conventional dosage forms in the art, preferably in the form of solid, semi-solid or liquid, and can be an aqueous solution, non-aqueous solution or suspension, more preferably tablets, capsules, granules, injections or infusions, etc.

[0019] Preferably, the pharmaceutical composition of the present invention further comprises one or more pharmaceutical carriers. The pharmaceutical carrier is a conventional pharmaceutical carrier in the art, and the pharmaceutical carrier can be any suitable physiologically or pharmaceutically acceptable pharmaceutical excipient. The pharmaceutical excipient is a conventional pharmaceutical excipient in the art, preferably including a pharmaceutically acceptable excipient, filler or diluent, etc. More preferably, the pharmaceutical composition comprises 0.01 to 99.99% of the above-mentioned protein and 0.01 to 99.99% of a pharmaceutical carrier, and the percentage is the mass percentage of the pharmaceutical composition.

[0020] Preferably, the amount of the pharmaceutical composition administered is an effective amount, which is an amount that can alleviate or delay the progression of a disease, degenerative or damaging condition. The effective amount can be determined on an individual basis and will be based in part on considerations of the symptoms to be treated and the results sought.

[0021] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0022] The reagents and raw materials used in the present invention are commercially available.

[0023] Beneficial technical effects: The polypeptide or polypeptide derivative of the present invention can target the TRIB3 / SRC interaction and promote the degradation of SRC and TRIB3 proteins, thereby being applied to the preparation of drugs for treating pancreatic cancer, liver cancer, and kidney cancer. The prepared drugs have the advantages of significant efficacy, few toxic side effects, and safe use in the treatment of tumor diseases. DETAILED DESCRIPTION

[0024] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0025] Unless otherwise specified, the PBS solution described in the examples refers to a phosphate buffer solution with a concentration of 1.0 μM and a pH value of 7.2.

[0026] The room temperature described in the examples is the conventional room temperature in the art, preferably 15-30°C.

[0027] The experimental results are expressed as mean ± standard error. After comparison with parametric or non-parametric variance test, p < 0.05 is considered to be significantly different, and p < 0.01 is considered to be extremely significantly different.

[0028] Example 1 Synthesis of polypeptide

[0029] The control peptide TAT is a universal cell-penetrating peptide with a known sequence. The amino acid sequence of SRC-1-2 is shown in the sequence table as SEQ ID No. 1. The control peptides TAT ​​and TAT-SRC-1-2 were synthesized and purified by Anhui Guoping Pharmaceutical Co., Ltd.

[0030] Table 1 Amino acid sequence list SEQ

[0031]

[0032] Experimental Example 2 Detection of the binding ability of peptides to TRIB3 protein using surface plasmon resonance

[0033] The surface plasmon resonance experiment was carried out in a surface plasmon resonance instrument Biacore T200, and the operation steps were carried out according to the instruction manual of the plasma resonance instrument Biacore T200. The specific steps are as follows:

[0034] 1. Purified TRIB3 protein (purchased from Sino Biological) was coupled to a CM5 chip (purchased from GE) via amino coupling, unbound protein was eluted at a flow rate of 10 μL / min, and the chip surface was equilibrated for 2 hours. For the specific steps of amino coupling, elution and equilibration, please refer to the relevant instructions of GE's CM5 chip.

[0035] 2. Automatic injection of 250 μL of different concentrations (2500, 1250, 62.5, 31.25, 15.62, 7.81, 3.9,

[0036] 1.95 and 0.975nM) of the TAT and TAT-SRC-1-2 polypeptide fragments prepared in Example 1, the entire surface plasmon resonance experiment was carried out at 25°C. The buffer used was HBS-EP buffer [0.01M HEPES, 0.15M NaCl, 3mM EDTA and 0.005% (w / w) surfactant]. The binding curves of different concentrations of peptides and TRIB3 were simulated using Biacore T200's own analysis software, and the affinity of the peptides and TRIB3 protein was calculated. Table 2 shows the affinity of the control peptide TAT, the peptide TAT-SRC-1-2 and the TRIB3 protein.

[0037] Table 2 Affinity test of TAT-SRC-1-2 and TRIB3 protein

[0038]

[0039] Experimental Example 3: Immunoblotting to verify that peptides disrupt TRIB3 / SRC interaction

[0040] 1. Collect human embryonic kidney cells HEK293T in the logarithmic growth phase, adjust the cell concentration with DMEM culture medium (purchased from Invitrogen, USA) to prepare a cell suspension of 200,000 cells / mL.

[0041] 2. Add 8 mL of the cell suspension prepared in step 1 to 100 cm 2 The culture dish was cultured, and after 12 hours, the culture medium was replaced with new culture medium, and 5 μg SRC-Myc and 5 μg TRIB3-HA eukaryotic expression plasmids were transferred into it.

[0042] 3. After culturing for 16 h, the culture medium was replaced with new complete medium and 10 μM of the polypeptide TAT-SRC-1-2 prepared in Example 1 was added.

[0043] 3.8 hours later, cells were collected and added with CoIP lysis buffer (purchased from Shanghai Bio-Tech Biotechnology Co., Ltd.) (add protease inhibitor PMSF and other inhibitors such as leupeptin and aprotinin before use according to the instruction manual), and lysed on ice for 30 min; centrifuged at 12000 rpm and 4°C for 30 min;

[0044] The supernatant was aspirated, HA antibody (purchased from Proteintech) was added, and the mixture was rotated at 4°C for 2 hours. Protein-A / G agarose was added, and the mixture was rotated at 4°C overnight.

[0045] 4. Centrifuge at 3000 rpm, 4°C for 5 min. Discard the supernatant and wash 5 times with CoIP lysis buffer. Add 2x loading buffer and denature at 98°C for 5 min.

[0046] 5. Take all samples and perform SDS-polyacrylamide gel electrophoresis according to the method described in "Molecular Cloning".

[0047] After electrophoresis, immunoblotting was performed.

[0048] 6. The immunoblotting results were quantitatively analyzed using Gel-Pro Analyzer32 Analyzer4.0 to calculate the percentage of reduction in TRIB3 / SRC interaction and determine whether the peptide can interrupt the TRIB3 / SRC interaction. The results are shown in Table 3. Table 3 shows that, compared with TAT, TAT-SRC-1-2 can interrupt the TRIB3 / SRC interaction.

[0049] Table 3 Effects of TAT-SRC-1-2 on TRIB3 / SRC interaction in the tool cell HERK293T exogenous transfection model

[0050]

[0051] Experimental Example 4: Immunoblotting experiment to verify the effect of peptides on the half-life of SRC and TRIB3 proteins

[0052] 1. Collect pancreatic cancer cells ASPC in the logarithmic growth phase and adjust the cell concentration with 1640 culture medium (purchased from Invitrogen, USA) to prepare a cell suspension of 200,000 cells / mL.

[0053] 2. Add 2 mL of the cell suspension prepared in step 1 to a 6-well plate for culture. After 12 hours, replace with new culture medium and add 10 μM TAT and TAT-SRC-1-2 prepared in Example 1, respectively.

[0054] 3. After 12 hours, protein synthesis inhibitor cycloheximide (CHX) was added at different time points, with the action time being 24h, 12h, 8h, 4h, 2h, and 0h, respectively. 10 μM TAT and TAT-SRC-1-2 prepared in Example 1 were added every 12h.

[0055] 4. Collect the cells, add RIPA lysis buffer (purchased from Shanghai Bio-Tech Biotechnology Co., Ltd.) (add protease inhibitor PMSF and other inhibitors such as leupeptin and aprotinin before use according to the instruction manual), lyse on ice for 30 minutes; centrifuge at 12000 rpm and 4°C for 30 minutes; aspirate the supernatant, quantify the protein by BCA method, adjust the protein to a uniform concentration according to the quantitative results, add 5× loading buffer, and denature at 98°C for 5 minutes.

[0056] 5. Take some samples and perform SDS-polyacrylamide gel electrophoresis according to the method described in "Molecular Cloning".

[0057] After electrophoresis, immunoblotting was performed.

[0058] 6. The immunoblotting results were quantitatively analyzed using Gel-Pro Analyzer32 Analyzer4.0, and the time-dependent SRC and TRIB3 content change curves were drawn to determine the time required for the SRC and TRIB3 protein content to drop to 50% of the 0h after CHX action, which was the half-life of SRC and TRIB3 proteins. The results are shown in Tables 5-6. Table 4-5 shows that compared with the control peptide, TAT-SRC-1-2 can significantly shorten the half-life of SRC and TRIB3 proteins.

[0059] Table 4 Effect of peptides on the half-life of cellular SRC protein

[0060]

[0061] Table 5 Effect of TAT-SRC-1-2 on the half-life of cellular TRIB3 protein

[0062]

[0063] Experimental Example 5 In vitro MTT experiment verifies that TAT-SRC-1-2 inhibits tumor cell proliferation

[0064] The operation steps are as follows:

[0065] 1. Collect pancreatic cancer cells ASPC-1, hepatoma cells MHCC97-H and renal cancer cells in the logarithmic growth phase

[0066] 769-P, RPMI 1640 (ASPC-1 and 769-P) and DMEM (MHCC97H) were used, respectively.

[0067] The cell concentration was adjusted with complete medium (purchased from Invitrogen, USA) to prepare a cell suspension of 30,000 / mL.

[0068] 2. The cell suspension prepared in step 1 was added to each well of a 96-well plate at 100 μL for culture, and 25, 12.5, 6.25, 3.13, 1.56, 0.78, and 0 μM TAT and TAT-SRC-1-2 prepared in Example 1 were added to the control group and the experimental group, respectively. The cells were cultured in a cell culture incubator.

[0069] 3. After 48 hours of peptide action, add 10 μL MTT to each well, mix well, continue to culture for 2-4 hours, discard the supernatant, and add 150 μL DMSO to fully dissolve.

[0070] 4. The absorbance values ​​of cell OD570 and OD720 were detected by microplate reader, and the cell growth curve was drawn in Graphpad according to the absorbance values. The results are shown in Table 6-9. The results in Table 6-9 show that TAT-SRC-1-2 inhibits the proliferation of pancreatic cancer cells ASPC-1, liver cancer cells MHCC97H, HUH7 and renal cancer cells 769-P in a concentration-dependent manner.

[0071] Table 6 TAT-SRC-1-2 inhibits the proliferation of pancreatic cancer cell ASPC-1

[0072]

[0073] Table 7 TAT-SRC-1-2 inhibits the proliferation of renal cancer cell 769-P

[0074]

[0075] Table 8 TAT-SRC-1-2 inhibits the proliferation of liver cancer cells MHCC97-H

[0076]

[0077] Table 9 TAT-SRC-1-2 inhibits the proliferation of liver cancer cells HUH7

[0078]

[0079] Experimental Example 6 In vitro spheroidization experiment verifies that TAT-SRC-1-2 inhibits tumor cell spheroidization in vitro

[0080] The operation steps are as follows:

[0081] 1. Collect pancreatic cancer cells ASPC-1, liver cancer cells HUH7 and renal cancer cells 769-P in the logarithmic growth phase, take appropriate amount of cells respectively, and resuspend them in StemXVivo Serum-Free Tumorsphere Media (purchased from R&D Company).

[0082] 2. Add 100 μL of the pancreatic cancer cell ASPC-1, liver cancer cell HUH7 and kidney cancer cell 769-P suspension prepared in step 1 to a low-adsorption 96-well plate (purchased from Corning) for culture. After 24 hours, add TAT and TAT-SRC-1-2 respectively. After continuing to culture for 5-7 days, count the number of microspheres formed.

[0083] The results are shown in Table 13. The results in Table 13 show that TAT-SRC-1-2 inhibits the formation of microspheres in pancreatic cancer cell ASPC-1, liver cancer cell HUH7 and renal cancer cell 769-P.

[0084] Table 13 Effect of TAT-SRC-1-2 on in vitro spheroidization of pancreatic cancer cell ASPC-1, liver cancer cell HUH7 and renal cancer cell 769-P (1000 cells)

[0085]

[0086] Experimental Example 7 Transwell assay verifies that TAT-SRC-1-2 inhibits tumor cell invasion and metastasis

[0087] The operation steps are as follows:

[0088] 1. Collect pancreatic cancer cells ASPC-1, liver cancer cells HUH7 and renal cancer cells 769-P in the logarithmic growth phase and spread them into 6-well plates. After 24 hours, add 6 μM TAT and TAT-SRC-1-2 respectively.

[0089] 2. Add polypeptide for 12 hours, remove serum, and starve cells overnight.

[0090] 3. The next day, apply Fibronectin (10 μg / mL) and Matrigel inside and outside the Transwell chamber in advance.

[0091] (1:8), and air-dry in a clean bench.

[0092] 4. Before adding cells, add serum-free culture medium to the Transwell chamber and hydrate at 37°C for 30 minutes.

[0093] The Transwell chamber was gently placed into a 24-well plate containing complete culture medium.

[0094] 5. Collect the starved cells and dilute them to a density of 1,000,000 / mL. Resuspend 100,000 cells in 0.4% FBS medium and carefully add them to the Transwell chamber.

[0095] 6. After 12 to 24 hours, discard the culture medium and wash once with PBS. Fix with 4% paraformaldehyde at room temperature for 20 minutes and wash three times with PBS. Stain with crystal violet staining solution at room temperature for 1 hour and wash three times with PBS. Observe and take pictures with an inverted microscope (magnification, ×200) and count the number of metastatic cells.

[0096] The results are shown in Table 14. The results show that TAT-SRC-1-2 inhibits tumor cell invasion and metastasis.

[0097] Table 14 TAT-SRC-1-2 inhibits tumor cell invasion and metastasis

[0098]

[0099] Experimental Example 8: Subcutaneous transplantation model experiment verifies that TAT-SRC-1-2 inhibits pancreatic cancer cell ASPC-1 tumor growth

[0100] The operation steps are as follows:

[0101] 1. Collect pancreatic cancer cells ASPC-1 in the logarithmic growth phase, adjust the cell concentration with PBS (purchased from Liweining Company) to prepare a cell suspension of 2000000 / mL.

[0102] 2. Nude mice were subcutaneously injected with 100 μL of cell suspension, with 10 animals in each group.

[0103] 3. On the second day of inoculation, TAT and TAT-SRC-1-2 were intraperitoneally injected at a dose of 5 mg / kg twice a week. Tumors were counted twice a week.

[0104] The results are shown in Table 15. The results in Table 15 show that TAT-SRC-1-2 inhibits the tumor growth of pancreatic cancer cell ASPC-1.

[0105] Table 15 TAT-SRC-1-2 inhibits pancreatic cancer cell ASPC-1 tumor growth

[0106]

Claims

1. A polypeptide or a derivative thereof, It is characterized in that The amino acid sequences of the polypeptides are the sequences shown in SEQ ID No.1 and SEQ ID No.

2.

2. The polypeptide or derivative thereof according to claim 1, It is characterized in that Routine modifications may be made to the polypeptide or its derivatives.

3. The polypeptide or derivative thereof according to claim 2, It is characterized in that The conventional modifications include acetylation, amidation, cyclization, glycosylation, phosphorylation, alkylation, biotinylation, fluorescent group modification, polyethylene glycol PEG modification, and immobilization modification.

4. The polypeptide or derivative thereof according to claim 2, It is characterized in that The derivatives include chimeric peptides formed by connecting the polypeptide and a cell-penetrating peptide, fusion peptides formed by the polypeptide and a virus, and methylated polypeptides.

5. Use of the polypeptide or derivatives thereof according to any one of claims 1 to 4 in the preparation of drugs for treating or preventing diseases related to SRC or TRIB3SRC.

6. Use of the polypeptide or derivatives thereof according to any one of claims 1 to 4 in the preparation of drugs for treating and / or preventing tumors.

7. The use according to claim 6, It is characterized in that The tumors are pancreatic cancer, liver cancer, and kidney cancer.

8. The use according to claim 7, It is characterized in that The pancreatic cancer includes pancreatic adenocarcinoma, exocrine gland carcinoma, ampullary carcinoma and endocrine pancreatic tumor; the liver cancer includes hepatocellular carcinoma; and the kidney cancer includes clear cell and papillary renal cell carcinoma.

9. A pharmaceutical composition, It is characterized in that It contains the polypeptide or its derivative according to any one of claims 1 to 4 and a biologically or pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition according to claim 9, It is characterized in that It contains the polypeptide or its derivative as claimed in any one of claims 1 to 4 as an active ingredient, or contains other compounds having anti-pancreatic cancer, liver cancer, and kidney cancer activities as active ingredients.

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