Materials and Methods Useful for Affecting Tumor Cell Growth, Migration and Invasion
AssigneeThe Ohio State University
InventorCarlo M. Croce
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Abstract
It is disclosed herein that miR-221 and miR-222 down-regulate PTEN and TIMP3 tumor suppressors, resulting in TRAIL resistance. The present invention provides research, diagnostic, and therapeutic tools and methods related to this discovery. Diagnostics, prognostics and treatments for human hepatocellular cancer and non-small cell lung carcinoma having a TRAIL resistance are particularly described herein.
Claims24
A method to alter the TRAIL Expression Pattern in a cell, comprising altering c-Jun, miR-221 and miR-222 and PTEN or TIMP3 in a cell capable of expressing c-Jun, miR-221 and miR-222, PTEN and TIMP3, and altering TRAIL Expression Pattern.
A method to identify the TRAIL Expression Pattern in a cell sample, comprising identifying expression levels of at least two nucleic acids in a cell sample, wherein the at least two are selected from the group consisting of:
- miR-221 and miR-222 and c-Jun;
- miR-221 and miR-222 and PTEN;
- miR-221, miR-222 and TIMP3;
- miR-221 and miR-222, c-Jun and PTEN;
- miR-221 and miR-222, PTEN and TIMP3;
- and miR-221 and miR-222, c-Jun and TIMP3;
- and identifying TRAIL expression in the cell sample.
A method to alter gene expression in a TRAIL-resistant cell, comprising altering miR-221 and miR-222 in a cell that also expresses at least one nucleic acid selected from the group consisting of:
- c-Jun;
- PTEN and TIMP3;
- and altering gene expression in the TRAIL-resistant cell.
A method to identify test cells having nucleic acid expression inhibition, comprising contacting at least one test cell with antisense miR-221 and miR-222;
- observing an increase in expression of a nucleic acid selected from the group consisting of:
- PTEN and TIMP3;
- and identifying the test cells having nucleic acid expression inhibition.
A method of predicting clinical outcome of a patient diagnosed with cancer, comprising detecting the expression level of miR-221 and miR-222 and at least one nucleic expression level of a nucleic acid selected from the group consisting of:
- c-Jun;
- PTEN and TIMP3, in a cancer cell sample obtained from the patient;
- and predicting clinical outcome, wherein a 1.5-fold or greater increase in the level of miR-221 and miR-222 in combination with a 1.5-fold or greater decrease in the level of PTEN or TIMP3 expression in the tumor sample relative to a control predicts a decrease in survival, or wherein a 1.5-fold or greater increase in the level of miR-221 and miR-222 in combination with a 1.5-fold or greater increase in the level of c-Jun expression in the tumor sample relative to a control predicts a decrease in survival.
A method to inhibit down-regulation of PTEN expression in a tumor cell that expresses miR-221 and miR-222 and PTEN, comprising inhibiting miR-221 and miR-222 activity in a tumor cell that expresses miR-221 and miR-222 and PTEN, and inhibiting PTEN down-regulation in the tumor cell.
A method to identify a therapeutic agent for the treatment of TRAIL-resistant cancer, comprising screening candidate agents in vitro to select an agent that decreases expression of miR-221 and miR-222 and increases expression of PTEN in a TRAIL-resistant cancer cell;
- and identifying a therapeutic agent for the treatment of TRAIL-resistant cancer.
A method to alter regulation of TIMP3 expression in a cell capable of expressing TIMP3 and miR-221 and miR-222, comprising altering miR-221 and miR-222 activity in a TIMP3-expressing and miR-221 and miR-222-expressing cell and altering regulation of TIMP3 expression.
A method to identify TRAIL-resistant cells, comprising identifying whether a test cell sample comprises miR-221 and miR-222 nucleic acid and TIMP3 nucleic acid;
- and identifying TRAIL-resistant cells.
A method to identify a therapeutic agent for the treatment of TRAIL-resistant cancer, comprising screening candidate agents in vitro to select an agent that decreases expression of miR-221 and miR-222 and increases expression of TIMP3 in a TRAIL-resistant cancer cell;
- and identifying an agent for the treatment of TRAIL-resistant cancer.
A method of predicting clinical outcome of a patient diagnosed with cancer, comprising:
- a) detecting the level of miR-221, miR-222 and TIMP3 expression in a cancer cell sample obtained from the patient, and b) predicting clinical outcome,
- wherein a 1.5-fold or greater increase in the level of miR-221 and miR-222 in combination with a 1.5-fold or greater decrease in the level of TIMP3 expression in the tumor sample relative to a control predicts a decrease in survival.
A method to inhibit down-regulation of TIMP3 expression in a tumor cell that expresses miR-221, miR-222 and TIMP3, comprising inhibiting miR-221 and miR-222 activity in a tumor cell that expresses miR-221, miR-222 and TIMP3 and inhibiting down-regulation of TIMP3 expression.
A method of claim 25, wherein TIMP3 expression down-regulation inhibition is observed via TIMP3 translation analysis.
Dependencies are inferred from the claim text.