C/EBPα short activating RNA compositions and methods of use

1. A method of modulating the expression of a gene in a cell comprising contacting the cell with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein said gene is selected from an oncogene or a tumor suppressing gene, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

2. The method of claim 1 , wherein the gene is an oncogene.

3. The method of claim 2 , wherein the expression of the oncogene is reduced.

4. The method of claim 3 , wherein the expression of the oncogene is reduced by at least 20%.

5. The method of claim 2 , wherein the gene is selected from the group consisting of ADAM17, AKT1, ANGPT2, BCL2, BCL2L1, BIRC2, BIRC5, CCL5, CCND1, CCND2, CDH1, CDH13, CDKN1A, CDKN1B, CDKN2A, CFLAR, CTNNB1, CXCR4, E2F1, EGF, EGFR, EP300, FADD, FLT1, FZD7, GSTP1, HGF, HRAS, IGFBP1, IGFBP3, IRS1, ITGB1, KDR, MCL1, MET, MSH2, MSH3, MTDH, MYC, NFKB1, NRAS, OPCML, PDGFRA, PIN1, PTGS2, PYCARD, RAC1, RASSF1, RELN, RHOA, SFRP2, SMAD7, SOCS1, STAT3, TCF4, TERT, TGFA, TGFB1, TLR4, TNFRSF10B, VEGFA, WT1, XIAP, and YAP1.

6. The method of claim 1 , wherein the gene is a tumor suppressing gene.

7. The method of claim 6 , wherein the expression of the tumor suppressing gene is increased.

8. The method of claim 7 , wherein the expression of the tumor suppressing gene is increased by a factor of at least 1.

9. The method of claim 6 , wherein the gene is selected from the group consisting of BAX, BID, CASP8, DAB21P, DLC1, FAS, FHIT, GADD45B, HHIP, IGF2, LEF1, PTEN, PTK2, RB1, RUNX3, SMAD4, SOCS3, TGFBR2, TNFBR2, TNFSF10, and P53.

10. The method of claim 1 , wherein the saRNA is double stranded and further comprises a sense strand.

11. A method of reducing the proliferation of hyperproliferative cells comprising contacting the cells with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

12. The method of claim 11 , wherein the hyperproliferative cells are tumor cells.

13. The method of claim 12 , wherein the hyperproliferative cells are liver tumor cells, breast cancer cells, leukemia cells, lymphoma cells, lung cancer cells, ovarian cancer cells, or pancreatic cancer cells.

14. The method of claim 11 , wherein the saRNA is double stranded and further comprises a sense strand.

15. A method of treating a hyperproliferative disorder comprising administering a composition comprising a therapeutically effective amount of a small activating RNA (saRNA) targeting a C/EBPα transcript to a subject in need thereof, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

16. The method of claim 15 , wherein the hyperproliferative disorder is tumor.

17. The method of claim 16 , wherein the tumor burden is reduced at least 10%.

18. The method of claim 16 , wherein the tumor is selected form a group consisting of hepatocellular carcinoma, breast cancer, lung cancer, leukemia, ovarian cancer, and pancreatic cancer.

19. The method of claim 18 , wherein the tumor is hepatocellular carcinoma.

20. The method of claim 18 , wherein the tumor is breast cancer.

21. The method of claim 20 , wherein the composition further comprises a siRNA that inhibits C/EBPβ gene expression.

22. The method of claim 15 , wherein the saRNA is double stranded and further comprises a sense strand.

23. The method of claim 21 , wherein the siRNA comprises SEQ ID No. 30 or 32.

24. A method of regulating the expression of a microRNA in a cell comprising contact the cell with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

25. The method of claim 24 , wherein the cell is a tumor cell.

26. The method of claim 25 , wherein the microRNA is an oncogenic microRNA.

27. The method of claim 26 , wherein the expression of the microRNAs is reduced.

28. The method of claim 27 , wherein the expression of the microRNA is reduced by at least 20%.

29. The method of claim 26 , wherein the microRNA is selected from hsa-miR-20b-5p, hsa-miR-125a-5p, hsa-miR-148b-3p, hsa-miR-92a-3p, hsa-miR-378a-3p, hsa-miR-130a-3p, hsa-miR-20a-5p, hsa-miR-132-3p, hsa-miR-193b-3p, hsa-miR-183-5p, hsa-miR-148a-3p, hsa-miR-138-5p, hsa-miR-373-3p, hsa-miR-29b-3p, hsa-miR-135b-5p, hsa-miR-21-5p, hsa-miR-181d, hsa-miR-301a-3p, hsa-miR-200c-3p, hsa-miR-7-5p, hsa-miR-29a-3p, hsa-miR-210, hsa-miR-17-5p, hsa-miR-98-5p, hsa-miR-25-3p, hsa-miR-143-3p, hsa-miR-19a-3p, hsa-miR-18a-5p, hsa-miR-125b-5p, hsa-miR-126-3p, hsa-miR-27a-3p, hsa-miR-372, hsa-miR-149-5p, and hsa-miR-32-5p.

30. The method of claim 25 , wherein the microRNA is a tumor suppressing microRNA.

31. The method of claim 30 , wherein the expression of the microRNA is increased.

32. The method of claim 31 , wherein the expression of the microRNA is increased by a factor of at least 1.

33. The method of claim 30 , wherein the microRNA is selected from hsa-let-7a-5p, hsa-miR-133b, hsa-miR-122-5p, hsa-miR-335-5p, hsa-miR-196a-5p, hsa-miR-142-5p, hsa-miR-96-5p, hsa-miR-184, hsa-miR-214-3p, hsa-miR-15a-5p, hsa-let-7b-5p, hsa-miR-205-5p, hsa-miR-181a-5p, hsa-miR-140-5p, hsa-miR-146b-5p, hsa-miR-34c-5p, hsa-miR-134, hsa-let-7g-5p, hsa-let-7c, hsa-miR-218-5p, hsa-miR-206, hsa-miR-124-3p, hsa-miR-100-5p, hsa-miR-10b-5p, hsa-miR-155-5p, hsa-miR-1, hsa-miR-150-5p, hsa-let-7i-5p, hsa-miR-27b-3p, hsa-miR-127-5p, hsa-miR-191-5p, hsa-let-7f-5p, hsa-miR-10a-5p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-144-3p, hsa-miR-128, hsa-miR-215, hsa-miR-193a-5p, hsa-miR-23b-3p, and hsa-miR-203a.

34. The method of claim 24 , wherein the saRNA is double stranded and further comprises a sense strand.

35. A method of treating non-alcoholic fatty liver disease, cirrhosis, insulin resistance or obesity comprising administering a composition comprising a therapeutically effective amount of a small activating RNA (saRNA) targeting a C/EBPα transcript to a patient in need thereof, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

36. The method of claim 35 , wherein the LDL level in liver cells of said patient is reduced.

37. The method of claim 35 , wherein the triglyceride level in liver cells of said patient is reduced.

38. The method of claim 35 , wherein the body weight of said patient is reduced.

39. The method of claim 35 , wherein the liver size of said patient is reduced.

40. The method of claim 35 , wherein the expression of FAT/CD36, SREBP1, DGAT2, CETP, FASN, PPARγ-CoA1α, PPARγ-CoA1β, or MLXIPL is reduced.

41. The method of claim 35 , wherein the expression of LPL, LXD, ACACA, ACACB, APOC3, MTP, LDLR, PGC-1α, PGC-1β, PPARγ, or PPARα is increased.

42. The method of claim 35 , wherein the saRNA is double stranded and further comprises a sense strand.

43. The method of claim 35 , wherein the white adipose tissue of said patient is reduced.

44. The method of claim 35 , wherein the brown adipose tissue of said patient is activated.

45. The method of claim 35 , wherein the body fat of said patient is reduced.

46. The method of claim 35 , wherein the serum albumin level of said patient is increased.

47. A method of regulating the expression of a pluripotency gene in a cell comprising contacting the cell with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

48. The method of claim 47 , wherein the cell is a stem cell.

49. The method of claim 47 , wherein the pluripotency gene is selected from SOX2, OCT4, cKit, KLF4, or NANOG.

50. The method of claim 47 , wherein the saRNA comprises SEQ ID. No. 2, 4, 6, 8, 10, 12, or 318.

51. A method of regulating epithelial-mesenchymal transition (EMT) in a cell comprising contact the cell with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

52. The method of claim 51 , wherein the cell is a tumor cell.

53. The method of claim 52 , wherein the cell is a hepatocellular carcinoma cell.

54. The method of claim 51 , wherein the saRNA up-regulates the expression of runt-related transcription factor-3 (RUNX3) gene.

55. The method of claim 51 , wherein the saRNA down-regulates the expression of a gene selected from hepatocyte growth factor (HGF) gene, small body size mothers against decapentaplegic homolog 7 (SMAD7) gene, transforming factor beta 1 (TGFB1) gene, or catenin beta 1 (CTNB1) gene.

56. The method of claim 51 , wherein the saRNA regulates at least one microRNA of the cell.

57. The method of claim 51 , wherein the saRNA is double stranded and further comprises a sense strand.

58. A method of increasing white blood cell count in a patient in need thereof comprising administering a composition comprising a therapeutically effective amount of a small activating RNA (saRNA) targeting a C/EBPα transcript to said patient, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

59. The method of claim 58 , wherein the saRNA is carried with a dendrimer.

60. The method of claim 59 , wherein the dendrimer is a poly(amidoamine) (PAMAM) dendrimer.

61. The method of claim 60 , wherein the PAMAM dendrimer has a DAB core.

62. The method of claim 58 , wherein the saRNA has a 2′-OMe-U modifications (mU) at 3′-terminus.

63. The method of claim 58 , wherein the saRNA is double stranded and further comprises a sense strand.

64. The method of claim 58 , wherein said patient has leukopaenia, sepsis, a chronic inflammation disease, hepatitis, or liver cirrhosis, is immunocompromised, or is under chemotherapy.

65. A method of regulating the ratio of isoforms of C/EBP proteins in a cell comprising contact the cell with a composition comprising a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

66. The method of claim 65 , wherein the cell is a HepG2 cell.

67. The method of claim 66 , wherein the C/EBP protein is a C/EBPα protein.

68. The method of claim 67 , wherein the 42 KDa isoform of the C/EBPα protein is increased.

69. The method of claim 65 , wherein the C/EBP protein is a C/EBPβ protein.

70. The method of claim 69 , wherein the 30 KDa isoform of the C/EBPβ protein is increased.

71. A method of upregulating extra coding CEBPA (ecCEBPA) comprising administering a small activating RNA (saRNA) targeting a C/EBPα transcript, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

72. A method of increasing liver regeneration rate of a patient after hepatectomy comprising administering a small activating RNA (saRNA) targeting a C/EBPα transcript to said patient, wherein the saRNA comprises an antisense strand of SEQ ID No. 318.

73. The method of claim 72 , the saRNA is administered before hepatectomy is performed.

74. The method of claim 72 , wherein the hepatectomy is partial hepatectomy.