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CN-122005599-A - Application of substance for inhibiting expression of deubiquitinase in preparation of pancreatic cancer treatment product

CN122005599ACN 122005599 ACN122005599 ACN 122005599ACN-122005599-A

Abstract

The invention belongs to the technical field of medicines and disease treatment, and particularly relates to application of a substance for inhibiting expression of deubiquitinase in preparation of a pancreatic cancer treatment product. The invention provides application of a substance for inhibiting expression of deubiquitinase USP36 in preparing a pancreatic cancer treatment product, wherein the amino acid sequence of the deubiquitinase USP36 is shown as SEQ ID NO. 1. The invention discovers that the silent deubiquitinase USP36 remarkably inhibits the killing capacity of pancreatic cancer cells against CD8 + T cells through screening a deubiquitinase RNA interference library for the first time. And it was found that USP36 promotes expression of PD-L1 by promoting deubiquitination of YAP protein, stabilizing YAP protein, thereby allowing more YAP/TEAD to bind to the enhancer region of PD-L1, and finally promoting immunization of pancreatic cancer cells.

Inventors

  • ZHU JIAN
  • ZHUANG TING
  • YANG HUIJIE
  • GUO HAOJIE
  • ZHANG SHUQING

Assignees

  • 河南医药大学

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. The application of a substance for inhibiting the expression of deubiquitinase USP36 in preparing a pancreatic cancer treatment product is characterized in that the amino acid sequence of the deubiquitinase USP36 is shown as SEQ ID NO. 1.
  2. 2. The use according to claim 1, characterized in that the nucleotide sequence of the nucleic acid encoding said deubiquitinase USP36 is shown in SEQ ID No. 2.
  3. 3. The use according to claim 1, wherein the substance inhibiting expression of deubiquitinase USP36 comprises siRNA.
  4. 4. The use according to claim 3, wherein the siRNA is selected from any one or more of siUSP36#1, siUSP36#2 and siUSP36 #3; the sense strand of siUSP #1 is shown as SEQ ID NO. 3; The sense strand of siUSP #2 is shown in SEQ ID NO. 5; the sense strand of siUSP #3 is shown in SEQ ID NO. 7.
  5. 5. The use according to claim 1, characterized in that said product has said substance inhibiting the expression of deubiquitinase USP36 as the sole active ingredient or one of the active ingredients.
  6. 6. The use according to claim 5, wherein when said product contains said substance inhibiting expression of deubiquitinase USP36 as one of the active ingredients, the active ingredients further comprise a chemotherapeutic agent.
  7. 7. The use according to claim 6, wherein the chemotherapeutic agent is selected from any one or more of gemcitabine, paclitaxel and 5-fluorouracil.
  8. 8. A medicament for treating pancreatic cancer, comprising the substance inhibiting expression of deubiquitinase USP36 according to claim 1.
  9. 9. The medicament of claim 8, wherein the substance that inhibits expression of deubiquitinase USP36 comprises siRNA.
  10. 10. The medicament of claim 8, wherein the siRNA is selected from any one or more of siUSP36#1, siUSP36#2, and siUSP36 #3; the sense strand of siUSP #1 is shown as SEQ ID NO. 3; The sense strand of siUSP #2 is shown in SEQ ID NO. 5; the sense strand of siUSP #3 is shown in SEQ ID NO. 7.

Description

Application of substance for inhibiting expression of deubiquitinase in preparation of pancreatic cancer treatment product Technical Field The invention belongs to the technical field of medicines and disease treatment, and particularly relates to application of a substance for inhibiting expression of deubiquitinase in preparation of a pancreatic cancer treatment product. Background Pancreatic cancer is commonly known as "king in cancer", and pancreatic ductal adenocarcinoma (PANCREATIC DUCTAL ADENOCARCINOMA, PDAC) is the most common pancreatic cancer, accounting for 95% of the incidence of pancreatic cancer. Early clinical symptoms of pancreatic cancer are not obvious, most patients are at advanced stage of the disease when they visit the clinic, and the survival rate of postoperative patients is extremely low. KRAS gene mutation (functional activation) is an important molecular pathology basis of pancreatic cancer, more than 90% of tumors in pancreatic cancer can find this type of mutation, and about 50% -80% of tumors can find TP53, CDKN2A and SMAD4 gene mutation (functional inactivation). At present, the treatment means of pancreatic cancer is very limited, radical surgical excision is a main treatment means of early pancreatic cancer, but more than 80% of patients find local advanced or distant metastasis at the time of first diagnosis, and only less than 20% of patients can receive surgical treatment. For advanced pancreatic patients, chemotherapy is mainly based, and radiotherapy and targeted therapy are combined. Despite the significant increase in research investment in methods of treating pancreatic cancer in recent years, the survival rate of pancreatic cancer for 5 years still does not exceed 10%. In recent years, with great success of cell surface apoptosis receptor-1 (PD-1) monoclonal antibody treatment in melanoma, immunotherapy has become a hotspot for malignant tumor treatment. While immunotherapy may be a new hope for future breakthroughs in pancreatic cancer treatment, current clinical data shows that immunotherapy has not been ideal for treatment in pancreatic cancer, which may be associated with the susceptibility of pancreatic cancer cells to immune escape. Therefore, further intensive research on the mechanism for regulating the occurrence and development of pancreatic cancer and easily generating immune escape, exploration of biological characteristics of pancreatic cancer cells different from normal cells and intervention are important directions for exploring effective treatment means of pancreatic cancer. Ubiquitin-protease system (UPS) is one of the important ways to regulate protein degradation. Deubiquitinase enzymes (deubiquitinating enzymes, DUBs) can reverse target protein degradation by cleaving ubiquitin chains or removing ubiquitin from modified substrates to modulate ubiquitin signaling. These enzymes can be largely divided into five families, the ubiquitin-specific protease (USP/UBP) family, the ubiquitin carboxy-terminal hydrolase (UCH) family, the OTU family, the Josephin domain protein family, and the JAMM family, depending on the DUBs active site. The most studied USP family at present becomes a novel drug action target point because the function of the USP family is clear. Deubiquitinase plays an important role in tumor immunity. For example, USP22 can directly interact with the C end of PD-L1 to induce the deubiquitination and stabilization of the PD-L1, so as to promote the immune escape of liver cancer cells. Recent studies indicate that deubiquitinase CSN5 can directly induce deubiquitination of PD-L1, and curcumin reduces the level of PD-L1 in cancer cells by inhibiting CSN5, so that the curative effect of anti-CTLA 4 treatment is improved. In recent years, with the advent of more and more targeted inhibitors of deubiquitinase, deubiquitinase may be a new potential target for improving the therapeutic effect of tumor immunotherapy. Therefore, there is a need to develop new applications of deubiquitinase in tumor immunotherapy. Disclosure of Invention In order to develop a new application of the deubiquitinase in tumor immunotherapy, the invention provides an application of a substance for inhibiting expression of the deubiquitinase in preparing a pancreatic cancer treatment product. In order to achieve the above purpose, the present invention adopts the following technical scheme. The invention aims to provide application of a substance for inhibiting expression of deubiquitinase USP36 in preparing a pancreatic cancer treatment product. The amino acid sequence of the deubiquitinase USP36 is shown in SEQ ID NO. 1. Preferably, the nucleotide sequence of the nucleic acid encoding said deubiquitinase USP36 is shown in SEQ ID No. 2. Preferably, the substance that inhibits expression of deubiquitinase USP36 comprises siRNA. Preferably, the transfection concentration of the siRNA is 20 nM-50 nM. Preferably, the siRNA is selected from any one or more of siUSP36#1, si