Metastasis is one of the key factors of treatment failure in late-stage colorectal cancer (CRC). Metastatic CRC frequently develops resistance to chemotherapeutic agents. This study aimed to identify the novel regulators from \"hidden\" proteins encoded by long noncoding RNAs (lncRNAs) involved in tumor metastasis and chemoresistance. Methods: CRISPR/Cas9 library functional screening was employed to identify the critical suppressor of cancer metastasis in highly invasive CRC models. Western blotting, immunofluorescence staining, invasion, migration, wound healing, WST-1, colony formation, gain- and loss-of-function experiments, in vivo experimental metastasis models, multiplex immunohistochemical staining, immunohistochemistry, qRT-PCR, and RT-PCR were used to assess the functional and clinical significance of FOXP3, PRDM16-DT, HNRNPA2B1, and L-CHEK2. RNA-sequencing, co-immunoprecipitation, qRT-PCR, RT-PCR, RNA affinity purification, RNA immunoprecipitation, MeRIP-quantitative PCR, fluorescence in situ hybridization, chromatin immunoprecipitation and luciferase reporter assay were performed to gain mechanistic insights into the role of PRDM16-DT in cancer metastasis and chemoresistance. An oxaliplatin-resistant CRC cell line was established by in vivo selection. WST-1, colony formation, invasion, migration, Biacore technology, gain- and loss-of-function experiments and an in vivo experimental metastasis model were used to determine the function and mechanism of cimicifugoside H-1 in CRC. Results: The novel protein PRDM16-DT, encoded by LINC00982, was identified as a cancer metastasis and chemoresistance suppressor. The down-regulated level of PRDM16-DT was positively associated with malignant phenotypes and poor prognosis of CRC patients. Transcriptionally regulated by FOXP3, PRDM16-DT directly interacted with HNRNPA2B1 and competitively decreased HNRNPA2B1 binding to exon 9 of CHEK2, resulting in the formation of long CHEK2 (L-CHEK2), subsequently promoting E-cadherin secretion. PRDM16-DT-induced E-cadherin secretion inhibited fibroblast activation, which in turn suppressed CRC metastasis by decreasing MMP9 secretion. Cimicifugoside H-1, a natural compound, can bind to LEU89, HIS91, and LEU92 of FOXP3 and significantly upregulated PRDM16-DT expression to repress CRC metastasis and reverse oxaliplatin resistance. Conclusions: lncRNA LINC00982 can express a new protein PRDM16-DT to function as a novel regulator in cancer metastasis and drug resistance of CRC. Cimicifugoside H-1 can act on the upstream of the PRDM16-DT signaling pathway to alleviate cancer chemoresistance.

Cell cycle regulation is an important cellular function. Abnormal regulation of this process can cause cancer. Several genes are involved in this process. There is no comprehensive study on expression pattern of cell cycle related lncRNAs in breast cancer patients. In the current study, we evaluated expressions of LINC00668, PRDM16-DT, SNHG7 and CDKN2A in 42 pairs of breast cancer tissues and adjacent non-tumoral tissues. Expression of SNHG7 was significantly lower in tumoral tissues compared with non-tumoral tissues. However, expressions of LINC00668, PRDM16-DT and CDKN2A were not significantly different between these two sets of samples. Expression levels of SNHG7 could separate tumoral tissues from non-tumoral tissues with AUC value= 0.66, sensitivity= 61% and specificity= 73%. Expression of CDKN2A was associated with clinical stage (P value=0.01). Expression levels of LINC00668, PRDM16-DT, SNHG7 and CDKN2A were higher in estrogen receptor (ER) positive samples compared with ER negative ones (P values=0.044, 0.008, 0.002 and 0.022, respectively). Moreover, expression of SNHG7 was higher in progesterone receptor (PR) positive samples compared with PR negative ones (P value=0.02). Finally, expressions of PRDM16-DT, SNHG7 and CDKN2A were higher in HER2/neu positive samples compared with HER2/neu negative ones (P values=0.017, 0.02 and 0.021, respectively). Taken together, our study demonstrates possible roles of these genes in breast cancer and warrants further functional studies.