Mutator Activity Induced by microRNA-155 (miR-155) Links Inflammation and Cancer

Abstract

Methods of reducing spontaneous mutation rate of a cell in a subject in need thereof by reducing endogenous levels of miR-155 are described.

What is claimed is: 
     
         1 . A method of modulating expression of a gene in an inflammation-related cancer target cell, the method comprising:
 administering a miR-155 antagonist to the target cell in an amount sufficient to modulate expression of at least one gene;   wherein the gene is APC, adenomatous polyposis coli; and,   wherein expression of the APC gene is increased after administration.   
     
     
         2 . The method of  claim 1 , wherein the miR-155 antagonist comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a sequence at least 80% identical to mature miR-155, pre-miR-155, a miR-155 seed sequence, or a sequence fully complementary to the sequence of mature miR-155, pre-miR-155, or miR-155. 
     
     
         3 . The method of  claim 2 , wherein the miR-155 antagonist comprises a modified oligonucleotide having no more than two mismatches to the nucleobase sequence of mature miR-155. 
     
     
         4 . The method of  claim 1 , wherein administering a miR-155 antagonist comprises:
 administering an antisense miR-155 expression vector to a target cell; and expressing an antisense miR-155 in the target cell.   
     
     
         5 . The method of  claim 1 , wherein the target is a breast cancer or precancerous cell. 
     
     
         6 . The method of  claim 1 , wherein the target cell is a colon cancer or precancerous cell. 
     
     
         7 . The method of  claim 1 , wherein the target cell is a gastric cancer or precancerous cell. 
     
     
         8 . The method of  claim 1 , wherein the target cell is a lung cancer or precancerous cell. 
     
     
         9 . The method of  claim 1 , comprising contacting the target cell with an antisense miR-155 inhibitory RNA (155-I), and wherein the expression levels of the at least one gene are increased after 155-I treatment. 
     
     
         10 . The method of  claim 1 , wherein the administration of the miR-155 antagonist reduces the miR-155 level in the target cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after miR-155 antagonist administration. 
     
     
         11 . The method of  claim 9 , wherein the administration of the 155-I reduces the miR-155 level in the cancer cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after 155-I administration. 
     
     
         12 . The method of  claim 1 , wherein the target cell is a human cell. 
     
     
         13 . A method of reducing spontaneous mutation rate of an inflammation-related solid cancer cell in a subject in need thereof, comprising:
 contacting the target cell with an antisense miR-155 inhibitory RNA (155-I) in an amount sufficient to increase the expression levels of at least one gene, wherein the expression levels are increased after 155-I treatment; and   wherein the at least one gene is APC, adenomatous polyposis coli.   
     
     
         14 . The method of  claim 13 , wherein the miR-155 antagonist comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a sequence at least 80% identical to mature miR-155, pre-miR-155, a miR-155 seed sequence, or a sequence fully complementary to the sequence of mature miR-155, pre-miR-155, or miR-155. 
     
     
         15 . The method of  claim 14 , wherein the miR-155 antagonist comprises a modified oligonucleotide having no more than two mismatches to the nucleobase sequence of mature miR-155. 
     
     
         16 . The method of  claim 13 , wherein administering a miR-155 antagonist comprises:
 administering an antisense miR-155 expression vector to a target cell; and expressing an antisense miR-155 in the target cell.   
     
     
         17 . The method of  claim 13 , wherein the target is a breast cancer or precancerous cell. 
     
     
         18 . The method of  claim 13 , wherein the target cell is a colon cancer or precancerous cell. 
     
     
         19 . The method of  claim 13 , wherein the target cell is a gastric cancer or precancerous cell. 
     
     
         20 . The method of  claim 13 , wherein the target cell is a lung cancer or precancerous cell. 
     
     
         21 . The method of  claim 13 , comprising contacting the target cell with an antisense miR-155 inhibitory RNA (155-I), and wherein the expression levels of the at least one gene are increased after 155-I treatment. 
     
     
         22 . The method of  claim 13 , wherein the administration of the miR-155 antagonist reduces the miR-155 level in the target cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after miR-155 antagonist administration. 
     
     
         23 . The method of  claim 21 , wherein the administration of the 155-I reduces the miR-155 level in the cancer cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after 155-I administration. 
     
     
         24 . The method of  claim 13 , wherein the target cell is a human cell. 
     
     
         25 . A method of preventing the onset of an inflammatory-related cancer, comprising:
 normalizing expression levels of at least one gene by reducing inflammatory-related up-regulation of miR-155 in a subject in need thereof,   by administering an antisense miR-155 inhibitory RNA (155-I) to a cell such that the resulting expression of miR-155 is normalized or elevated by no more than two-fold as compared with a control level of miR-155 expression, and wherein the gene expression levels are increased after 155-I treatment,   wherein the at least one gene is APC, adenomatous polyposis coli.   
     
     
         26 . The method of  claim 25 , wherein the antisense miR-155 inhibitory RNA (155-I) comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a sequence at least 80% identical to mature miR-155, pre-miR-155, a miR-155 seed sequence, or a sequence fully complementary to the sequence of mature miR-155, pre-miR-155, or miR-155. 
     
     
         27 . The method of  claim 26 , wherein the antisense miR-155 inhibitory RNA (155-I) comprises a modified oligonucleotide having no more than two mismatches to the nucleobase sequence of mature miR-155. 
     
     
         28 . The method of  claim 25 , wherein administering the antisense miR-155 inhibitory RNA (155-I) comprises: administering an antisense miR-155 expression vector to a target cell; and
 expressing an antisense miR-155 in the target cell.   
     
     
         29 . The method of  claim 25 , wherein the target is a breast cancer or precancerous cell. 
     
     
         30 . The method of  claim 25 , wherein the target cell is a colon cancer or precancerous cell. 
     
     
         31 . The method of  claim 25 , wherein the target cell is a gastric cancer or precancerous cell. 
     
     
         32 . The method of  claim 25 , wherein the target cell is a lung cancer or precancerous cell. 
     
     
         33 . The method of  claim 25 , comprising contacting the target cell with antisense miR-155 inhibitory RNA (155-I), and wherein the expression levels of the at least one gene are increased after 155-I treatment. 
     
     
         34 . The method of  claim 25 , wherein the administration of the antisense miR-155 inhibitory RNA (155-I) reduces the miR-155 level in the target cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after miR-155 antagonist administration. 
     
     
         35 . The method of  claim 33 , wherein the administration of the antisense miR-155 inhibitory RNA (155-I) reduces the miR-155 level in the cancer cell from greater than four-fold to less than two-fold as compared with a control level of miR-155, wherein the control level is derived from a non-cancerous cell, and wherein the expression levels of the at least one gene are increased after 155-I administration. 
     
     
         36 . The method of  claim 25 , wherein the target cell is a human cell. 
     
     
         37 . The method of  claim 25 , wherein the cell further comprises a cell exhibiting at least one mutation selected from the group comprising: the mutations listed in  FIG. 12  (SEQ ID NOS: 9-123).