Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells.

Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long-standing recognition of the crosstalk between carcinoma-associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer-associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA-ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β-catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.

Deng X ，Ruan H ，Zhang X ，Xu X ，Zhu Y ，Peng H ，Zhang X ，Kong F ，Guan M ... -  《-》

Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19.

Ren J ，Ding L ，Zhang D ，Shi G ，Xu Q ，Shen S ，Wang Y ，Wang T ，Hou Y ... -  《Theranostics》

CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer.

Hu JL ，Wang W ，Lan XL ，Zeng ZC ，Liang YS ，Yan YR ，Song FY ，Wang FF ，Zhu XH ，Liao WJ ，Liao WT ，Ding YQ ，Liang L ... -  《Molecular Cancer》

Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α.

Long non-coding RNAs (lncRNAs) are emerging as key molecules in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression and functions of lncRNAs in the development of colorectal cancer (CRC). LncRNA expression profiling of CRC, adenoma and normal colorectal tissues was performed to identify tumour-related lncRNAs involved in colorectal malignant transformation. Then, we used quantitative reverse transcription PCR assays to measure the tumour-related lncRNA and to assess its association with survival and response to adjuvant chemotherapy in 252 patients with CRC. The mechanisms of CCAL function and regulation in CRC were examined using molecular biological methods. We identified colorectal cancer-associated lncRNA (CCAL) as a key regulator of CRC progression. Patients whose tumours had high CCAL expression had a shorter overall survival and a worse response to adjuvant chemotherapy than patients whose tumours had low CCAL expression. CCAL promoted CRC progression by targeting activator protein 2α (AP-2α), which in turn activated Wnt/β-catenin pathway. CCAL induced multidrug resistance (MDR) through activating Wnt/β-catenin signalling by suppressing AP-2α and further upregulating MDR1/P-gp expression. In addition, we found that histone H3 methylation and deacetylases contributed to the upregulation of CCAL in CRC. Our results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression.

Ma Y ，Yang Y ，Wang F ，Moyer MP ，Wei Q ，Zhang P ，Yang Z ，Liu W ，Zhang H ，Chen N ，Wang H ，Wang H ，Qin H ... -  《-》

The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signaling.

Han P ，Li JW ，Zhang BM ，Lv JC ，Li YM ，Gu XY ，Yu ZW ，Jia YH ，Bai XF ，Li L ，Liu YL ，Cui BB ... -  《Molecular Cancer》