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CN-122005862-A - Application of MYSM to control ITPR1 mediated autophagy in inhibiting cervical cancer

CN122005862ACN 122005862 ACN122005862 ACN 122005862ACN-122005862-A

Abstract

The invention discloses an application of MYSM < 1> to control ITPR 1-mediated autophagy in inhibiting cervical cancer, which belongs to the technical field of biological medicine, and the invention activates MYSM-ITPR 1-autophagy signal paths by up-regulating the expression or activity of MYSM < 1> genes and/or encoding proteins thereof so as to inhibit proliferation, migration, invasion or epithelial-mesenchymal transition of cervical cancer cells and/or promote apoptosis of cervical cancer cells, wherein MYSM < 1> activates expression of ITPR1 by means of the activity of ubiquitination modified by lysine at 119 th site of histone H2A, and the ITPR1 is used as an endoplasmic reticulum calcium ion channel to mediate calcium ion release so as to trigger autophagy of the cells. Based on the mechanism, the invention provides a novel application of MYSM/ITPR 1 in preparing anti-cervical cancer drugs, a drug composition targeting the pathway, a candidate drug screening method and a kit for diagnosing prognosis, and aims to solve the problem that the prior art lacks a technical scheme for targeting MYSM-ITPR 1 pathway to effectively inhibit malignant progress of cervical cancer.

Inventors

  • CHEN XU
  • LI YUFANG
  • WANG TAO
  • JIA LINTAO

Assignees

  • 中国人民解放军空军军医大学
  • 陕西省人民医院(陕西省临床医学研究院)

Dates

Publication Date
20260512
Application Date
20260130

Claims (10)

  1. 1. Use of a MYSM gene and/or its encoded protein in the manufacture of a medicament for inhibiting the malignant progression of cervical cancer, characterized by activating the MYSM-ITPR 1-autophagy signaling pathway by up-regulating the expression or activity of said MYSM gene and/or its encoded protein, thereby inhibiting proliferation, migration, invasion or epithelial-mesenchymal transition of cervical cancer cells, and/or promoting apoptosis of cervical cancer cells; Wherein, MYSM1 activates the expression of ITPR1 through the activity of the deubiquitination enzyme modified by lysine monoubiquitination at 119 th site of histone H2A, and ITPR1 is used as an endoplasmic reticulum calcium ion channel to mediate calcium ion release so as to trigger autophagy of cells.
  2. 2. The use of MYSM gene and/or its encoded protein in the manufacture of a medicament for inhibiting the malignant progression of cervical cancer according to claim 1, wherein the nucleotide sequence of MYSM gene is represented by NCBI RefSeq database accession No. NM-015079.4, encoding MYSM1 protein comprising SANT domain, SWIRM domain and JAMM deubiquitinase catalytic domain.
  3. 3. The use of MYSM gene and/or its encoded protein according to claim 1 in the manufacture of a medicament for inhibiting the progression of malignancy of cervical cancer, wherein expression of ITPR1 is directly transcriptionally activated by upstream epigenetic regulator MYSM1, MYSM1 being transcribed by removal of H2AK119ub1 modification in the region near the transcription initiation site of ITPR1 gene.
  4. 4. The use of MYSM gene and/or its encoded protein in the manufacture of a medicament for inhibiting the malignant progression of cervical cancer according to claim 1, wherein the ITPR1 gene and/or its encoded protein responds to MYSM1 modulation by mediating calcium ion release from the endoplasmic reticulum, thereby up-regulating the expression of autophagy initiation factor Beclin1 and promoting lipidation conversion of LC3-I to LC 3-II.
  5. 5. The use of MYSM gene and/or its encoded protein according to claim 4 for the preparation of a medicament for inhibiting the malignant progression of cervical cancer, wherein the nucleotide sequence of the ITPR1 gene is as shown in NCBI RefSeq database accession No. NM-002222.5, and the encoded ITPR1 protein is a transmembrane glycoprotein localized in the endoplasmic reticulum, comprising a ligand binding domain, a central regulatory domain and a C-terminal transmembrane domain, said C-terminal transmembrane domain forming a hexameric calcium channel complex.
  6. 6. A pharmaceutical composition for inhibiting malignant progression of cervical cancer, based on the use of one MYSM gene and/or its encoded protein according to any one of claims 1-5 in the manufacture of a medicament for inhibiting malignant progression of cervical cancer, characterized by comprising an effective dose of an active ingredient and a pharmaceutically acceptable carrier or adjuvant; The active ingredient is selected from any one or more of a recombinant MYSM1 expression vector, a MYSM1 mRNA delivery system, a MYSM1 expression up-regulator, an ITPR1 activator and a recombinant ITPR1 expression vector; The carrier or the auxiliary material is selected from water for injection, normal saline, phosphate buffer solution, mannitol, sucrose, polysorbate, poloxamer or trehalose, and the pharmaceutical composition is in the form of injection, freeze-dried powder injection or intratumoral slow-release implant.
  7. 7. The pharmaceutical composition for inhibiting malignant progression of cervical cancer according to claim 6, wherein the MYSM mRNA delivery system uses lipid nanoparticles as a carrier, the ITPR1 activator is a small molecule compound, and the pharmaceutical composition is prepared into oral tablets or capsules.
  8. 8. A method of screening a candidate drug for activating MYSM-ITPR 1-autophagy pathway to inhibit cervical cancer, based on the use of a MYSM1 gene and/or encoded protein thereof according to any one of claims 1-5 in the manufacture of a drug for inhibiting malignant progression of cervical cancer, comprising the steps of: Providing a cervical cancer cell screening model for stably expressing a reporter gene, wherein the expression of the reporter gene is regulated and controlled by MYSM or an ITPR1 promoter; Applying a test compound to the screening model at a gradient concentration; Detecting and quantifying the mRNA expression level of MYSM1, the deubiquitinase activity of MYSM1, the protein expression level of ITPR1, or the intracellular LC3-II/LC3-I ratio; If the test compound can simultaneously up-regulate MYSM1 expression or activity and ITPR1 expression in a dose-dependent manner, the test compound is judged to be a positive candidate drug.
  9. 9. Use of a kit for detecting MYSM-ITPR 1 pathway states in cervical cancer, based on a MYSM gene and/or its encoded protein according to any of claims 1-5, for the manufacture of a medicament for inhibiting the malignant progression of cervical cancer, characterized in that it comprises reagents for detecting the expression and/or activity of MYSM1 and ITPR 1.
  10. 10. A kit for detecting the status of MYSM-ITPR 1 pathways in cervical cancer according to claim 9, wherein the reagents comprise qPCR primer pairs and/or probes for quantitatively detecting MYSM mRNA and ITPR1 mRNA and/or antibodies specifically recognizing MYSM protein and ITPR1 protein.

Description

Application of MYSM to control ITPR1 mediated autophagy in inhibiting cervical cancer Technical Field The invention relates to the technical field of biological medicines, in particular to an application of MYSM < 1 > to control of ITPR 1-mediated autophagy in inhibiting cervical cancer. Background Cervical cancer is a serious disease threatening global female health, clinical treatment mainly depends on operation, radiotherapy and platinum chemotherapy, but the traditional methods have common problems of obvious toxic and side effects, easy generation of drug resistance, limited curative effect on advanced patients and the like. Therefore, the molecular mechanism for cervical cancer occurrence and development is deeply explored, and new therapeutic targets and prognosis markers are sought, so that the urgent need for promoting the accurate therapeutic development is met. In recent years, the interaction of epigenetic regulation with autophagy has been increasingly emphasized in tumor progression. MYSM 1A is a key epigenetic regulator with histone H2A deubiquitinase activity, plays a core role in maintaining genome stability and hematopoietic system function, and is primarily found to have cancer inhibition potential in models of colon cancer and the like. Meanwhile, ITPR1, which is a calcium ion release channel of the endoplasmic reticulum, is disclosed as a key factor for regulating the initiation of autophagy, which affects the progress of tumors by inducing protective autophagy in tumors such as renal cell carcinoma. However, in highly heterogeneous cervical cancers, the expression patterns, functions and clinical significance of MYSM and ITPR1, respectively, are lacking in systematic studies. The prior technical means for inhibiting cervical cancer mainly extend around the tradition and the improvement scheme thereof. The operation excision is suitable for early patients, but has the problems of large wound, influence on fertility function and the like, the radiation therapy can locally control focus but can cause irreversible damage to surrounding normal tissues to cause long-term complications, and the platinum chemotherapy represented by cisplatin is a basic stone scheme of late and recurrent patients, but has serious nephrotoxicity, neurotoxicity and almost unavoidable multi-drug resistance, so that the curative effect and the life quality of the patients are greatly limited. Existing therapies have focused on direct killing of tumor cells or mobilization of the immune system, with insufficient intervention of the endogenous regulatory network of tumor cells, particularly dynamic, complex signaling axes like epigenetic-metabolism. The lack of such intervention, which results in a treatment strategy often lacking specificity, makes it difficult to accurately distinguish the functional dependence of cancerous cells from normal cells, and thus creates a bottleneck in efficacy and an accumulation of toxicity. Disclosure of Invention The invention overcomes the defects of the prior art and provides an application of MYSM1 to control of ITPR1 mediated autophagy in inhibiting cervical cancer. In order to achieve the aim, the technical scheme adopted by the invention is that MYSM1 regulates and controls the application of ITPR1 mediated autophagy in inhibiting cervical cancer, and the application comprises the following steps: Use of a MYSM gene and/or its encoded protein in the manufacture of a medicament for inhibiting the malignant progression of cervical cancer, characterized by activating the MYSM-ITPR 1-autophagy signaling pathway by up-regulating the expression or activity of said MYSM gene and/or its encoded protein, thereby inhibiting proliferation, migration, invasion or epithelial-mesenchymal transition of cervical cancer cells, and/or promoting apoptosis of cervical cancer cells; Wherein, MYSM1 activates the expression of ITPR1 through the activity of the deubiquitination enzyme modified by lysine monoubiquitination at 119 th site of histone H2A, and ITPR1 is used as an endoplasmic reticulum calcium ion channel to mediate calcium ion release so as to trigger autophagy of cells. In a preferred embodiment of the present invention, the nucleotide sequence of MYSM gene is shown in NCBI RefSeq database accession No. NM-015079.4, which encodes a MYSM protein comprising a SANT domain, a SWIRM domain, and a JAMM deubiquitinase catalytic domain. In a preferred embodiment of the present invention, the expression of ITPR1 is directly activated by transcription of the upstream epigenetic regulator MYSM, MYSM1 is transcribed by removing the H2AK119ub1 modification in the region near the transcription initiation site of the ITPR1 gene. In a preferred embodiment of the present invention, the ITPR1 gene and/or its encoded protein responds to MYSM1 regulation, by mediating calcium ion release from the endoplasmic reticulum, thereby up-regulating expression of the autophagy initiation factor Beclin1 and promotin