PCDH1 interference preparation and application thereof in preparation of pancreatic cancer drugs

Abstract

The invention belongs to the technical field of pancreatic cancer drugs, and particularly relates to a PCDH1 interference preparation and application thereof in preparation of pancreatic cancer drugs. The PCDH1 interference preparation is a preparation for reducing the expression level of PCDH1; the PCDH1 interference preparation is a Chinese holly water decoction or a mixed water decoction of Chinese holly and patrinia herb, and the mixed water decoction of Chinese holly and patrinia herb is a water decoction prepared by mixing Chinese holly and patrinia herb according to equal mass. It is found for the first time that the folium ilicis purpurea water decoction or the folium ilicis purpurea and herba patriniae mixed water decoction has the effect of reducing the PCDH1 expression level, proliferation of pancreatic cancer cell lines BxPC-3 and Panc-1 can be inhibited, and the prospect of treating pancreatic cancer is achieved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pancreatic cancer drugs, and particularly relates to a PCDH1 interference preparation and application thereof in preparation of a pancreatic cancer drug. BACKGROUND

[0002] Protocadherin (PCDH) is a new type of cadherin, which is the largest subfamily in the cadherin superfamily. Protocadherin 1 (PCDH1) is a protein encoded by the protocadherin subfamily of the cadherin superfamily, which is a membrane protein found at cell-cell boundaries. PCDH1 includes an extracellular region containing 7 cadherin-like domains, a transmembrane region and a C-terminal cytoplasmic region. Cells expressing the protein exhibit cell aggregation activity.

[0003] PCDH1 is involved in neural cell adhesion and expressed in the nervous system, and is involved in the development of neuronal synapses and the formation of neural circuits, indicating that it may play a role in neuronal development and be related to neurological disorders such as epilepsy.

[0004] PCDH1 is also related to various cancer diseases. Genetic variations of PCDH1 can cause cancer, and abnormal expression of PCDH1 in tumors has also been concerned, which can be used as a biomarker for cancer prognosis and treatment. Pancreatic adenocarcinoma (PAAD) is an invasive solid tumor characterized by few early symptoms, high mortality and lack of effective treatment, so it is very important to determine new potential therapeutic targets and prognostic biomarkers for PAAD. Studies have shown that PCDH1 may be related to pancreatic cancer, such as significant differences in expression of PCDH1 in pancreatic cancer cells and normal cells.

[0005] Therefore, it is necessary to develop an interference preparation that affects the expression of PCDH1 to have a beneficial effect on the treatment of diseases, especially for the treatment of pancreatic cancer. SUMMARY

[0006] In order to solve the above technical problems, the application provides a PCDH1 interference preparation and application thereof in preparation of a pancreatic cancer drug.

[0007] The application aims to provide a PCDH1 interference preparation, which is a water decoction of Ilex hainanensis or a water decoction of a mixture of Ilex hainanensis and Patrinia scabiosae.

[0008] Among them, the four seasons are a kind of traditional Chinese medicine, bitter, astringent, cool, lung, large intestine, bladder, the existing technology often used for clearing heat and resolving toxicity, swelling and pain. The four seasons of water decoction are used to inhibit the expression of PCDH1, and then inhibit the proliferation of pancreatic cancer cells.

[0009] The herba patriniae is a kind of traditional Chinese medicine, cool, bitter and pungent; It has the effects of clearing heat and resolving toxicity, eliminating sputum and pus, and is often used for intestinal abscess, lung abscess, dysentery, postpartum blood stasis abdominal pain, abscess and boils. The present application is compounded with four seasons to inhibit the expression of PCDH1, and then inhibit the proliferation of pancreatic cancer cells.

[0010] The research results of the present application show that PCDH1 high expression is an independent risk factor for poor prognosis of pancreatic cancer patients, therefore the PCDH1 interference preparation provided by the present application refers to the preparation for reducing the expression level of PCDH1.

[0011] Preferably, the four seasons of water decoction are prepared according to the following method:

[0012] The four seasons of water decoction are crushed into 60-80 mesh four seasons powder, 8-10 times the mass of water is added to the four seasons powder, boiled for 20-30 min, the dregs are removed by filtration, and the filtrate is collected, which is the four seasons of water decoction.

[0013] Preferably, the four seasons of water decoction are prepared according to the following method:

[0014] The four seasons and herba patriniae are crushed into 60-80 mesh powder, mixed in equal quality to obtain traditional Chinese medicine powder, 8-10 times the mass of water is added to the traditional Chinese medicine powder, boiled for 20-30 min, the dregs are removed by filtration, and the filtrate is collected, which is the four seasons and herba patriniae mixed water decoction.

[0015] Preferably, 100-200 mesh filter screen is used for filtration to remove the dregs and retain the active ingredients with small molecular weight, and the water decoction prepared by this filtration method is convenient to make into injection or oral liquid.

[0016] The present application also provides a kind of PCDH1 interference preparation in the preparation of pancreatic cancer drugs.

[0017] Preferably, the pancreatic cancer drug further comprises a pharmaceutically acceptable excipient. The excipient, although not an active ingredient for treating diseases, plays a vital role in the storage, transportation, etc. of the drug. For example, (1) some excipients have the functions of antioxidation and preservation, such as the addition of antioxidants such as vitamin C and sodium sulfite to avoid the inactivation of the active ingredients of the drug due to oxidation during storage; the addition of methyl paraben (methyl nipagin) and other preservatives can inhibit microbial growth and prolong the shelf life of the drug; (2) some excipients have the function of adjusting the environment, such as the addition of a buffer (such as a phosphate buffer) to maintain the pH value of the drug solution stable and prevent the degradation of the active ingredients of the drug due to changes in the acid-base environment; the use of an osmotic pressure regulator (such as sodium chloride) makes the osmotic pressure of the drug close to that of the human body fluid, reducing the irritation to the gastrointestinal tract; (3) some excipients can improve the drug dosage form, such as solubilizers (such as polysorbate-80) that can help the uniform dispersion of poorly soluble main drugs in the solution to avoid precipitation.

[0018] It should be noted that the main inventive concept of the present application is to provide a PCDH1 interfering preparation and its application in the preparation of a pancreatic cancer drug, wherein the pancreatic cancer drug takes the PCDH1 interfering preparation as the active ingredient, and the corresponding excipient is not limited, as long as it is allowed to be used in pharmacy and does not chemically react with the PCDH1 interfering preparation.

[0019] Preferably, the excipient is water for injection, which is inexpensive, easy to obtain, and has high safety.

[0020] Preferably, the excipient is a solubilizer, such as ethanol or polyethylene glycol, which is a common excipient and has high safety.

[0021] Preferably, the pancreatic cancer drug comprises the PCDH1 interfering preparation and other therapeutic drugs, and the other therapeutic drugs are at least one of gemcitabine and albumin paclitaxel.

[0022] Gemcitabine (alias gemcitabine hydrochloride for injection) is a new cytosine nucleoside derivative, which is a pyrimidine antitumor drug. Its main metabolite is incorporated into DNA in cells to inhibit DNA synthesis, mainly acting on the G1 / S phase.

[0023] Albumin paclitaxel (alias paclitaxel albumin for injection) is used for the treatment of various cancers (such as breast cancer, lung cancer, pancreatic cancer, etc.). Its advantage lies in the fact that it does not need to use a solvent that is prone to sensitization, thereby reducing the risk of allergy, and can more efficiently target tumor tissues through the transport mechanism of albumin.

[0024] The combination of multiple pancreatic cancer drugs has a more obvious effect on resisting pancreatic cancer.

[0025] It should be noted that the pancreatic cancer drugs include PCDH1 interfering agents combined with other therapeutic drugs, which can be prepared into composite drugs by adding adjuvants or prepared separately and combined for use. The present application does not require that the PCDH1 interfering agent is miscible with other therapeutic drugs.

[0026] Preferably, the pancreatic cancer drug refers to a drug for inhibiting the proliferation of pancreatic cancer cells.

[0027] Preferably, the pancreatic cancer cells are at least one of pancreatic cancer cell strains BxPC-3 and Panc-1.

[0028] Compared with the prior art, the present application has the following beneficial effects:

[0029] 1. The present application first discovers that the water decoction of Ilex hainanensis or the water decoction of Ilex hainanensis mixed with Patrinia scabiosae has the effect of reducing the expression level of PCDH1. In vitro experiments show that, compared with normal cells, the water decoction of Ilex hainanensis or the water decoction of Ilex hainanensis mixed with Patrinia scabiosae can significantly reduce the PCDH1 expression level of pancreatic cancer cell strains BxPC-3 and Panc-1.

[0030] 2. The present application first discovers that the water decoction of Ilex hainanensis or the water decoction of Ilex hainanensis mixed with Patrinia scabiosae can inhibit the proliferation of pancreatic cancer cell strains BxPC-3 and Panc-1, and has the prospect of treating pancreatic cancer.

[0031] 3. The present application first proposes a preparation method of a pancreatic cancer drug taking PCDH1 interfering agents as the only active ingredient, and can also increase adjuvants on the basis of PCDH1 interfering agents to prepare a pancreatic cancer drug such as an injection or an oral preparation.

[0032] 4. The present application also provides the inventive concept of compounding PCDH1 interfering agents with existing pancreatic cancer treatment drugs, and the anticancer effect will be more obvious in the case of combination of multiple pancreatic cancer drugs. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 PCDH1 expression is significantly up-regulated in pancreatic cancer;

[0034] Wherein, a is the database statistical result, b is the histopathological grading result, c is the qPCR result, d1 is the normal pancreatic tissue immunohistochemical result, d2 is the pancreatic cancer tissue immunohistochemical result, and e is the ROC result.

[0035] Figure 2 PCDH1 expression is negatively correlated with the survival rate of pancreatic cancer;

[0036] Wherein, a is overall survival rate, b is disease-free survival rate, c is ROC result, d is single factor COX regression analysis result of PCDH1 and other clinical pathological characteristics, e is multi-factor COX regression analysis result of PCDH1 and other clinical pathological characteristics.

[0037] Figure 3 PCDH1-siRNA silencing efficiency verification related results;

[0038] Wherein, a is qPCR result, b is Western Blot result.

[0039] Figure 4 CCK-8 experiment results and Transwell results;

[0040] Wherein, a is CCK-8 experiment result, b1 is Transwell result of siRNA-NC, b2 is Transwell result of siRNA-2, b3 is Transwell result of siRNA-3.

[0041] Figure 5 Cell scratch experiment results;

[0042] Wherein, the first row is the result of cell scratch experiment 0h, the second row is the result of cell scratch experiment 48h, the first column is siRNA-NC, the second column is siRNA-2, and the third column is siRNA-3.

[0043] Figure 6 PCDH1 regulates CD8+T cell infiltration related results;

[0044] Wherein, a is the result at protein level, and b is CD8+T cell recruitment experiment result.

[0045] Figure 7 Results of PCDH1 experiment using the drug of the application. DETAILED DESCRIPTION

[0046] In order to enable those skilled in the art to better understand the technical solutions of the present application and to implement them, the present application will be further described below in conjunction with specific embodiments and drawings.

[0047] In the description of the present application, if not specially stated, the reagents used are commercially available, and the methods used are conventional techniques in the art.

[0048] The present application has made research on the correlation between original cadherin 1 (PCDH1) and pancreatic cancer in the early stage, found that PCDH1 is highly expressed in pancreatic cancer, the expression level of PCDH1 is significantly negatively correlated with the number of tumor infiltrating CD8+T cells, and PCDH1 knockdown can significantly regulate lipid metabolism by activating AMPK signaling pathway.

[0049] Specific results are as follows:

[0050] (1) PCDH1 has high accuracy as a diagnostic marker for pancreatic cancer

[0051] Bioinformatics analysis showed that PCDH1 was significantly highly expressed in pancreatic cancer tissues in TCGA and HPA databases, P<0.001, which was verified in pancreatic cancer cell lines. For related results, see Figure 1 . Figure 1 In the above formula, a is a database statistical result, and by searching TCGA database and GTEx database to analyze pancreatic cancer tissues and normal pancreatic tissues, it is found that PCDH1 is significantly up-regulated in pancreatic cancer; Figure 1 In the above formula, b is a histopathological grading result, and the pancreatic cancer tissues in TCGA are grouped according to histopathological grading, and it is found that the expression of PCDH1 is up-regulated with the increase of the degree of differentiation; Figure 1 In the above formula, c is a qPCR result, and the qPCR result shows that PCDH1 is significantly up-regulated in multiple pancreatic cancer cell lines, while normal pancreatic duct epithelial cells almost do not express PCDH1 (qPCR result is represented by ΔCT); d1 is the immunohistochemical result of normal pancreatic tissue, d2 is the immunohistochemical result of pancreatic cancer tissue, and e is the ROC result, the AUC of PCDH1 for diagnosing pancreatic cancer is 0.978, CI: 0.966-0.991, indicating that PCDH1 has very high diagnostic performance.

[0052] (2) PCDH1 expression level is closely related to the prognosis of pancreatic cancer patients

[0053] According to the median level of PCDH1, pancreatic cancer patients are divided into Low PCDH1 and High PCDH1, and Kaplan-Meier survival analysis shows that compared with the low expression group of PCDH1, the overall survival (OS) and disease-free survival (DFS) of patients in the high expression group of PCDH1 are significantly shortened, see Figure 2 a and b. Time-dependent ROC curve analysis shows that the prediction AUC values of PCDH1 expression level on the 1-year, 3-year and 5-year survival rates of pancreatic cancer patients are 0.641, 0.682 and 0.754 respectively, see Figure 2 c. In addition, combined with clinical pathological characteristics (including age, gender, degree of differentiation, clinical stage, T stage and N stage, etc.), single factor and multiple factor analysis are carried out by Cox proportional hazards regression model, and the results show that high expression of PCDH1 is an independent risk factor for poor prognosis of pancreatic cancer patients, see Figure 2 d and e.

[0054] (3) Quantitative PCR (qRT-PCR) and Western blot analysis

[0055] The present application designs two siRNA sequences for silencing PCDH1, including siRNA-2 and siRNA-3.

[0056] The sequence of siRNA-2 is as follows:

[0057] Sense strand, SEQ ID NO. 1: GCUCUAAUGCUGAGCUGGUUUTT;

[0058] Antisense strand, SEQ ID NO. 2: AAACCAGCUCAGCAUUAGAGCTT.

[0059] The sequence of siRNA-3 is as follows:

[0060] Sense strand, SEQ ID NO. 3: GCUUUGAUCGAGAGCAACAAATT;

[0061] Antisense strand, SEQ ID NO. 4: UUUGUUGCUCUCGAUCAAAGCTT.

[0062] To verify the PCDH1 interference efficiency, we verified the expression inhibition effect of PCDH1 at the transcriptional and protein levels by real-time quantitative PCR (qRT-PCR) and Western blot analysis, respectively. To avoid the off-target effect of RNAi, we selected two effective interference sequences (siRNA-2 and siRNA-3). The results showed that, compared with the control group (siRNA-NC) without adding interference sequence, both siRNA-2 and siRNA-3 could significantly reduce the expression of PCDH1. For related results, see Figure 3 .

[0063] (4) Biological function of PCDH1 in pancreatic cancer cells

[0064] To explore the biological function of PCDH1 in pancreatic cancer cells, we carried out a series of functional experiments by siRNA-mediated gene silencing method. CCK-8 detection showed that PCDH1 silencing significantly inhibited the proliferation activity of pancreatic cancer cells, and the results are shown in Figure 4 a; Transwell experiment showed that the invasion ability of cells in the PCDH1 silencing group was significantly reduced, and the results are shown in Figure 4 b1-b2; cell scratch test further confirmed that PCDH1 silencing significantly reduced the migration ability of pancreatic cancer cells, and the results are shown in Figure 5 . These results indicate that PCDH1 plays an important role in regulating the malignant phenotype of pancreatic cancer cells.

[0065] (5)PCDH1 is involved in immune regulation

[0066] To explore whether PCDH1 is involved in immune regulation, first of all, according to the TCGA database, the expression of PCDH1 is negatively correlated with CD8+ T infiltration by using CIBERSORT algorithm analysis; then it is found that the high expression of PCDH1 in ductal epithelial cells is significantly negatively correlated with the proportion of CD8+ T cells at the single cell level, and this result is verified at the tissue level. The CD8+ T cell recruitment experiment also confirms that knocking down PCDH1 reduces the inhibition of CD8+ T cell recruitment, which suggests that PCDH1 may not only accelerate the progression of pancreatic cancer by regulating lipid metabolism, but also promote tumor immune escape by weakening the anti-tumor immune function. For related results, see Figure 6 .

[0067] Based on the above research, the present application provides a PCDH1 interfering preparation and its application in the preparation of a pancreatic cancer drug, including the following inventive concepts:

[0068] (1) The PCDH1 interfering preparation refers to a preparation that reduces the expression level of PCDH1; the PCDH1 interfering preparation is a water decoction of Ilex hainanensis, or a mixed water decoction of Ilex hainanensis and Patrinia scabiosae fisch.

[0069] (2) The application of the PCDH1 interfering preparation in the preparation of a pancreatic cancer drug is manifested as inhibition of the proliferation of pancreatic cancer cells. The pancreatic cancer drug can be a PCDH1 interfering preparation as the only active ingredient, or can be compounded with other therapeutic drugs, wherein the other therapeutic drugs are at least one of gemcitabine and albumin paclitaxel.

[0070] The present application includes the following specific examples.

[0071] Example 1

[0072] A PCDH1 interfering preparation is a water decoction of Ilex hainanensis, which is prepared according to the following method:

[0073] The water decoction of Ilex hainanensis is crushed into Ilex hainanensis powder of 60 mesh, 8 times the mass of water is added to the Ilex hainanensis powder, boiled for 20 min, filtered with a 100 mesh filter screen to remove the dregs, and the filtrate is collected, which is the water decoction of Ilex hainanensis.

[0074] Example 2

[0075] A PCDH1 interfering preparation is a water decoction of Ilex hainanensis, which is prepared according to the following method:

[0076] The four seasons green water decoction is crushed into 80 mesh four seasons green powder, 8 times the mass of water is added to the four seasons green powder, boiled for 20 min, 100 mesh filter screen is used to remove the drug residue, and the filtrate is collected, which is the four seasons green water decoction.

[0077] Example 3

[0078] A PCDH1 interfering preparation is four seasons green water decoction, which is prepared according to the following method:

[0079] The four seasons green water decoction is crushed into 60 mesh four seasons green powder, 10 times the mass of water is added to the four seasons green powder, boiled for 20 min, 100 mesh filter screen is used to remove the drug residue, and the filtrate is collected, which is the four seasons green water decoction.

[0080] Example 4

[0081] A PCDH1 interfering preparation is four seasons green water decoction, which is prepared according to the following method:

[0082] The four seasons green water decoction is crushed into 60 mesh four seasons green powder, 8 times the mass of water is added to the four seasons green powder, boiled for 30 min, 100 mesh filter screen is used to remove the drug residue, and the filtrate is collected, which is the four seasons green water decoction.

[0083] Example 5

[0084] A PCDH1 interfering preparation is four seasons green and patrinia mixed water decoction, wherein the four seasons green and patrinia mixed water decoction is prepared according to the following method:

[0085] The four seasons green and patrinia are both crushed into 60 mesh powder, the same mass of the two is mixed to obtain traditional Chinese medicine powder, 8 times the mass of water is added to the traditional Chinese medicine powder, boiled for 20 min, 200 mesh filter screen is used to remove the drug residue, and the filtrate is collected, which is the four seasons green and patrinia mixed water decoction.

[0086] Example 6

[0087] A PCDH1 interfering preparation is four seasons green and patrinia mixed water decoction, wherein the four seasons green and patrinia mixed water decoction is prepared according to the following method:

[0088] The four seasons green and patrinia are both crushed into 80 mesh powder, the same mass of the two is mixed to obtain traditional Chinese medicine powder, 8 times the mass of water is added to the traditional Chinese medicine powder, boiled for 20 min, 200 mesh filter screen is used to remove the drug residue, and the filtrate is collected, which is the four seasons green and patrinia mixed water decoction.

[0089] Example 7

[0090] A PCDH1 interference preparation is a mixed water decoction of Ilex asprella and Herba Patriniae, wherein the mixed water decoction of Ilex asprella and Herba Patriniae is prepared according to the following method:

[0091] Ilex asprella and Herba Patriniae are both crushed into 60-mesh powder, and the traditional Chinese medicine powder is obtained by mixing the powders in equal quality; water is added to the traditional Chinese medicine powder in an amount of 10 times the mass of the traditional Chinese medicine powder, and boiled for 20 min; the residue is removed by filtering through a 200-mesh filter screen, and the filtrate is collected, thereby obtaining the mixed water decoction of Ilex asprella and Herba Patriniae.

[0092] Example 8

[0093] A PCDH1 interference preparation is a mixed water decoction of Ilex asprella and Herba Patriniae, wherein the mixed water decoction of Ilex asprella and Herba Patriniae is prepared according to the following method:

[0094] Ilex asprella and Herba Patriniae are both crushed into 60-mesh powder, and the traditional Chinese medicine powder is obtained by mixing the powders in equal quality; water is added to the traditional Chinese medicine powder in an amount of 8 times the mass of the traditional Chinese medicine powder, and boiled for 30 min; the residue is removed by filtering through a 200-mesh filter screen, and the filtrate is collected, thereby obtaining the mixed water decoction of Ilex asprella and Herba Patriniae.

[0095] Example 9

[0096] A pancreatic cancer drug is a mixed water decoction of Ilex asprella and gemcitabine hydrochlorate for injection, and the volume ratio of the two is 1:1; the two drugs are prepared separately and mixed when used.

[0097] The mixed water decoction of Ilex asprella is prepared according to the following method:

[0098] The mixed water decoction of Ilex asprella is crushed into 60-mesh Ilex asprella powder, water is added to the Ilex asprella powder in an amount of 8 times the mass of the Ilex asprella powder, and boiled for 20 min; the residue is removed by filtering through a 100-mesh filter screen, and the filtrate is collected, thereby obtaining the mixed water decoction of Ilex asprella.

[0099] Example 10

[0100] A pancreatic cancer drug is a mixed water decoction of Ilex asprella and white albumin paclitaxel, and the volume-mass ratio of the mixed water decoction of Ilex asprella and white albumin paclitaxel is 50:1; the two drugs are prepared separately and mixed when used.

[0101] The mixed water decoction of Ilex asprella is prepared according to the following method:

[0102] The mixed water decoction of Ilex asprella is crushed into 60-mesh Ilex asprella powder, water is added to the Ilex asprella powder in an amount of 8 times the mass of the Ilex asprella powder, and boiled for 20 min; the residue is removed by filtering through a 100-mesh filter screen, and the filtrate is collected, thereby obtaining the mixed water decoction of Ilex asprella.

[0103] Example 11

[0104] A pancreatic cancer drug is a mixed water decoction of four seasons green and patrinia and injection of gemcitabine hydrochloride, and the volume ratio of the two is 1:1.

[0105] The mixed water decoction of four seasons green and patrinia is prepared according to the following method:

[0106] The four seasons green and patrinia are both crushed into 60-mesh powder, mixed in equal quality to obtain traditional Chinese medicine powder, 8 times the mass of water is added to the traditional Chinese medicine powder, boiled for 20 min, filtered with a 100-mesh filter screen to remove the dregs, and the filtrate is collected, which is the mixed water decoction of four seasons green and patrinia.

[0107] I. In vitro pancreatic cancer cell inhibition test is as follows:

[0108] (1) Materials: pancreatic cancer cell strain BxPC-3 and pancreatic cancer cell strain Panc-1, and human normal pancreatic duct cells hTERT-HPNE.

[0109] (2) Method: When the above-mentioned pancreatic cancer cell strain BxPC-3, pancreatic cancer cell strain Panc-1 and human normal pancreatic duct cells hTERT-HPNE are cultured to 85% confluence, different drug treatments are performed on the cells, and incubation is performed for 4 days. Sterile distilled water is used as a blank control.

[0110] The different drug treatment experimental groups are shown in Table 1.

[0111] Table 1 Different drug treatment experimental groups

[0112]

[0113] (3) Results:

[0114] Each test is set to be treated in triplicate, and the average value of cell migration and invasion results is taken. The results in Table 2 show that experimental groups 1-11 can well inhibit the growth of pancreatic cancer cells.

[0115] Table 2 Cell growth inhibition rate results

[0116]

[0117] In order to prove the inhibition effect on PCDH1, the present application selects example 1 and example 5 as representatives, and the amount is 150 μL / kg of mice. β-actin is used as an internal reference to perform Western Blot test to test the expression amount of PCDH1. The results are shown in Figure 7 , examples 1 and 5 can inhibit the expression of PCDH1.

[0118] It should be noted that when the present application refers to a numerical range, it is understood that each numerical range has two endpoints and any number between the two endpoints can be selected. Since the same method of steps and examples are used, the preferred embodiments are described in the present application to prevent redundancy. Although the preferred embodiments of the present application have been described, those skilled in the art who have the inventive concept of the present application can make additional changes and modifications to the embodiments, and these changes and modifications fall within the scope of the present application.

[0119] Obviously, various modifications and changes can be made to the present application by those skilled in the art without departing from the spirit and scope of the present application. If these modifications and changes of the present application fall within the scope of the equivalent technology of the present application, the present application also intends to include these modifications and changes.

Claims

1. A PCDHl interfering agent, characterized in that, The PCDH1 interfering preparation refers to a preparation for reducing the expression level of PCDH1. The PCDH1 interfering preparation is a water decoction of Ilex hainanensis or a water decoction of Ilex hainanensis mixed with Patrinia.

2. The PCDHl interfering agent of claim 1, wherein, The water decoction of Ilex hainanensis is prepared by the following method: The water decoction of Ilex hainanensis is prepared by the following method:

3. The PCDHl interfering agent of claim 1, wherein the agent is a polynucleotide. The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

4. The PCDHl interfering agent of claim 2 or 3, wherein the agent is a polynucleotide. The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

6. The use of the PCDHl interfering agent according to claim 1 in the preparation of a drug for pancreatic cancer, characterized in that, The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

7. The use of the PCDHl interfering agent according to claim 6 in the preparation of a drug for pancreatic cancer, characterized in that, The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

8. The use of the PCDHl interfering agent according to claim 7 in the preparation of a drug for pancreatic cancer, characterized in that, The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

9. The use of the PCDHl interfering agent according to claim 5 in the preparation of a drug for pancreatic cancer, characterized in that, The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method:

10. The use of the PCDHl interfering agent according to claim 6 in the preparation of a drug for pancreatic cancer, characterized in that, The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainanensis mixed with Patrinia is prepared by the following method: The water decoction of Ilex hainan

Images