Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

Abstract

The tumor suppressor microRNA-199b (miR-199b) is a negative SET regulator associated with poor outcome in some human cancers. However, its expression levels as well as potential biological and clinical significance in colorectal cancer (CRC) remain completely unexplored. The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC (mCRC) but the molecular mechanisms underlying SET deregulation are currently unknown. We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients. Moreover, miR-199b led to PP2A activation through a direct SET inhibition, impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells. MiR-199b was found downregulated in 25% of cases, and associated with lymph metastasis (p = 0.049), presence of synchronous metastasis at diagnosis (p = 0.026) and SET overexpression (p < 0.001). Furthermore, low miR-199b levels determined shorter overall (p < 0.001), progression-free survival (p = 0.003) and predicted clinical benefit to oxaliplatin treatment. The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups. Multivariate analyses confirmed its independent prognostic impact. Altogether, our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patients.

Downregulation of miR‐199a/b‐5p is associated with GCNT2 induction upon epithelial–mesenchymal transition in colon cancer

“…These results strongly suggest that downregulation of miR‐199 is at least partly responsible for the observed induction of GCNT2 upon EMT of colon cancer cells. Consistent with these results, the levels of miR‐199 family members are downregulated in metastatic lesions in contrast with the primary tumor as seen in clinical samples of colon cancers, and miR‐199 suppresses colon cancer metastasis in vivo . It has been suggested that the miR‐199 family regulates the progression and metastasis of various cancers other than colon cancer, including liver, ovarian, prostate, and breast cancers .…”

Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review

“…MiR-181a 31–33 , miR-16 34–36 and miR-133b 37–39 were individually investigated in three studies. MiR-126 8, 40 , miR-133a 41, 42 , miR-182 43, 44 , miR-183 45, 46 , miR-199b 47, 48 , miR-22 49, 50 , miR-224 51, 52 , miR-24-3p 53, 54 , miR-7 55, 56 , were separately analyzed in two studies. Seven researches studied two miRs concomitantly 30, 34, 38, 39, 57–59 , while the others analyzed a single miR.…”

“…A total of 32 studies demonstrated the association between the downregulation of 32 miRs and the presence of lymph node metastasis such as miR-6852 106 , miR-302c 67 , miR-466 68 , miR-340 69 , miR-944 71 , miR-30d 72 , miR-22 50 , miR-296 73 , miR-199b 47 , let-7a-5p 98 , miR-132 99 , miR-497 107 , miR-206 100 , miR-128 75 , miR-154 78 , miR-149 79 , miR-24-3p 54 , miR-15a 34 , miR-16 34, 36 , miR-193a-5p 108 , miR-100 81 , miR-133a 41 , miR-205 109 , miR-335 82 , miR-378 101 , miR-218 83 , miR-138 110 , miR-625 111 , miR-212 112 , miR-195 113 , miR-133b 37 and miR-30c 103 . Other 30 studies verified the upregulation of miR-1296 84 , miR-200c 114 , miR-21 26, 29 , miR-130a 85 , miR-7 55 , miR-96 86 , miR-1260b 115 , miR-517a 87 , miR-106b 88 , miR-320e 89 , miR-196a 57 , miR-196b 57 , miR-376a 116 , miR-720 91 , miR-494 61 , miR-630 92 , miR-181a 31 , miR-20a 62 , miR-210 93 , miR-182 43, 44 , miR-25 94 , miR-191 95 , miR-183 46 , miR-199a-3p 117 , miR-429 105 , miR-92a 96 , miR-10b 118 , miR-155 30 and miR-552 97 associated with the presence of lymph node metastasis.…”

“…Among the evaluated studies, 49 demonstrated the downregulation of miR-199b 47, 48 , miR-6852 106 , miR-302c 67 , miR-466 68 , miR-650 123 , miR-196b-5p 70 , miR-944 71 , miR-30d 72 , miR-296 73 , miR-187 124 , let-7a-5p 98 , miR-132 99 , miR-206 100 , miR-148a 125 , miR-33b 76 , miR-99b-5p 120 , miR-154 78 , miR-217 126 , miR-149 79 , miR-194 80 , miR-7 56 , miR-24-3p 54 , miR-29b 127 , miR-15a 34 , miR-16 34, 36 , miR-204-5p 128 , miR-96-5p 121 , miR-193a-5p 108 , miR-100 81 , miR-133a 41 , miR-139-5p 129 , miR-124-5p 130 , miR-335 82 , miR-378 101 , miR-126 40 , miR-378a-3p 58 , miR-378a-5p 58 , miR-218 83 , miR-138 110 , miR-625 111 , miR-212 112 , miR-124 131 , miR-22 49 , miR-133b 39 , miR-193a-3p 104 , miR-195 113 and miR-30c 103 associated with worse prognosis (lower overall survival) of CRC patients. Fifty-six studies identified the upregulation of miR-181a 31–33 , miR-182 43, 44 , miR-1296 84 , miR-888 64 , miR-28-5p 132 , miR-183 45, 46 , miR-200c 114 , miR-34a 133 , miR-15a-5p 134 , miR-181c 135 , miR-24-3p 53 , miR-16 35 , miR-7 55 , miR-96 86 , miR-1260b 115 , miR-20a-5p 63 , miR-517a 87 , miR-503 136 , miR-106b 88 , miR-211 137 , miR-320e 89 , miR-592 90 , miR-196a 57 , miR-196b 57 , miR-376a …”

“…In total, 17 studies demonstrated the downregulation of 18 miRs associated with worse disease free-survival such as miR-196b-5p 70 , miR-944 71 , miR-30d 72 , miR-22 50 , miR-296 73 , miR-199b 47 , miR-187 124 , let-7a-5p 98 , miR-132 99 , miR-29b 127 , miR-15a 34 , miR-16 34 , miR-34a-5p 65 , miR-193a-5p 108 , miR-138 110 , miR-126 8 , miR-212 112 and miR-124 131 . Twenty-one studies associated the upregulation of miR-888 64 , miR-28-5p 132 , miR-183 45 , miR-200c 114 , miR-34a 133 , miR-15a-5p 134 , miR-181c 135 , miR-24-3p 53 , miR-16 35 , miR-96 86 , miR-1260b 115 , miR-20a-5p 63 , miR-517a 87 , miR-503 136 , miR-106b 88 , miR-320e 89 , miR-196a 57 , miR-196b 57 , miR-224 51 , miR-494 61 , miR-181a 32 , miR-21 25, 26, 30 and miR-155 30 with worse disease free-survival.…”