ABSTRACT Long intergenic non-coding RNA 152 (_LINC00152_) is a recently identified tumor-promoting long non-coding RNA. However, the biological functions of _LINC00152_ in colorectal cancer

(CRC) remain unclear and require further research. The aim of the present study is to explore the roles of _LINC00152_ in cellular function and its possible molecular mechanism. In this

study, we discovered that _LINC00152_ was overexpressed in CRC tissues and negatively related to the survival time of CRC patients. Functional analyses revealed that _LINC00152_ could

promote cell proliferation. Furthermore, _LINC00152_ could increase the resistance of CRC cells to 5-fluorouracil (5-FU) by suppressing apoptosis. We also discovered that _LINC00152_ could

VIEWED BY OTHERS LONG NON-CODING RNA LINC00511 FACILITATES COLON CANCER DEVELOPMENT THROUGH REGULATING MICRORNA-625-5P TO TARGET WEE1 Article Open access 27 April 2022 _LINC02257_ REGULATES

MALIGNANT PHENOTYPES OF COLORECTAL CANCER VIA INTERACTING WITH MIR-1273G-3P AND YB1 Article Open access 18 December 2024 SILENCING LONG NON-CODING RNA CASC9 INHIBITS COLORECTAL CANCER CELL

PROLIFERATION BY ACTING AS A COMPETING ENDOGENOUS RNA OF MIR-576-5P TO REGULATE AKT3 Article Open access 31 October 2020 INTRODUCTION Colorectal cancer (CRC) is the third most common cancer

worldwide1. The occurrence and development of CRC involve a series of complex changes at the genetic and epigenetic levels2. Increasing number of studies have demonstrated that long

non-coding RNAs (lncRNAs) are involved in the occurrence and development of CRC3. LncRNAs are a kind of RNA molecules with more than 200 nucleotides and no protein translation ability.

Recent advances have revealed the vital roles of lncRNAs in regulating tumorigenesis, and progression. Long intergenic non-coding RNA 152 (_LINC00152_) locates on chromosome 2p11.2 with 828 

nt transcription length. _LINC00152_ was overexpressed in tumor tissues and plasma of gastric cancer (GC) patients, and could promote GC cell proliferation and cell cycle progression through

regulating EGFR and EZH24,5,6,7. _LINC00152_ also plays an oncogenic role in liver8, gallbladder9, and lung cancer10. In addition, _LINC00152_ is likely to be an indicator of stress in a

variety of cells11. These studies exhibit the key oncogenic role and complicated mechanisms of _LINC00152_ in cancers. However, the detailed functions and mechanisms of _LINC00152_ in CRC

are mainly unclear. In this study, we showed that _LINC00152_ was upregulated in CRC, and correlated with poor survival. Functional analyses showed that _LINC00152_ could enhance CRC growth,

metastasis, and chemoresistance. Mechanistic studies demonstrated that _LINC00152_ promotes tumorigenesis and progression via working as a competitive endogenous RNA (ceRNA) of miR-139-5p,

which is a key tumor suppressive microRNA (miRNA)12,13,14,15,16,17,18. The present work reveals a novel regulatory pathway of _LINC00152_/miR-139-5p/NOTCH1 in CRC, suggesting that

_LINC00152_ is a new prognostic factor and potential therapeutic target in CRC. RESULTS OVEREXPRESSION OF _LINC00152_ IN CRC ASSOCIATES WITH POOR PROGNOSIS To study the role of _LINC00152_

in CRC, we first detected its expression in 108 paired CRC tissues and noncancerous tissues (NCTs). The results revealed that _LINC00152_ was obviously upregulated in CRC (_P_ < 0.001,

Fig. 1a), and 46.3% (50 of 108) of the CRC tissues showed > 2-fold upregulation of _LINC00152_ compared with their NCTs (Fig. 1b). To assess the potential association of _LINC00152_ with

clinicopathological features, we first divided the 108 patients into _LINC00152_-high and -low groups. We found that the _LINC00152_ levels in CRCs were significantly correlated with tumor

stage (_P_ = 0.013), whereas no obvious correlation between _LINC00152_ expression and other clinicopathological parameters was observed (Table 1). The survival analysis showed that patients

in the _LINC00152_-high group showed a shorter survival time than those in the _LINC00152_-low group (46.614 ± 3.366 vs. 69.338 ± 3.271 months; log rank = 9.456, _P_ = 0.0021, Fig. 1c). In

addition, high _LINC00152_ expression was also associated with poor disease-free survival (log rank = 4.383, _P_ = 0.0363, Fig. 1d). Furthermore, multivariate analysis further identified

that _LINC00152_ was an independent prognosis factor for CRC (hazard ratio (HR) = 2.514, 95% confidence interval (CI) = 1.125-5.621, _P_ = 0.025, Table 2). _LINC00152_ PROMOTES CRC CELL

PROLIFERATION The expression analyses of _LINC00152_ in six CRC cell lines showed that LoVo and SW480 have relatively high expressions of _LINC00152_, whereas HCT116 and HT29 have relatively

low expressions of _LINC00152_ (Fig. 2a). To investigate the biological functions of _LINC00152_ in CRC, we overexpressed _LINC00152_ in HCT116 and HT29 cells, and inhibited _LINC00152_

expression in LoVo and SW480 cells (Fig. 2b). We observed that _LINC00152_ overexpression significantly promoted CRC cell proliferation and colony formation. In contrast, decreased cell

growth, and colony formation abilities were showed in _LINC00152_-silenced cells (Fig. 2c–e). Furthermore, ectopic _LINC00152_ expression promoted CRC tumor growth _in vivo_ (Fig. 2f). All

these data reveal the growth-stimulating functions of _LINC00152_ in CRC. _LINC00152_ PROMOTES CELL CYCLE PROGRESSION AND CONFERS RESISTANCE TO 5-FU-INDUCED APOPTOSIS To investigate the

mechanism mediating the growth-promoting functions of _LINC00152_ in CRC, we measured the cell cycle distribution in the _LINC00152_-overexpressed and silenced CRC cells. As shown in Fig. 

3a, ectopic _LINC00152_ expression resulted in an increased number of cells in S phase, whereas _LINC00152_ knockdown caused a decreased cell number in S phase, indicating the promotion of

the cell cycle by _LINC00152_. 5-fluorouracil (5-FU) is a basic drug for CRC treatment, and we evaluated the effect of _LINC00152_ on 5-FU sensitivity in CRC cells. After overexpression or

knockdown of _LINC00152_, CRC cells were then assayed for their sensitivity to 5-FU by a CCK-8 assay. The results showed that ectopic _LINC00152_ expression decreased the sensitivity of

HCT116 cells to 5-FU, whereas _LINC00152_ silencing increased the sensitivity to 5-FU in LoVo cells (Fig. 3b). Given the key role of apoptosis in cancer chemotherapy, we further measured the

effect of _LINC00152_ on 5-FU-induced apoptosis. The results showed that the _LINC00152_ overexpression significantly antagonize 5-FU-induced apoptosis, whereas the _LINC00152_ knockdown

could augment apoptosis caused by 5-FU (Fig. 3c). _LINC00152_ PROMOTES CRC CELL MIGRATION AND INVASION Transwell assays were then performed to measure the impact of _LINC00152_ on CRC

metastasis. We observed that ectopic _LINC00152_ expression significantly facilitated migration and invasion in HCT116 cells (Fig. 4a), whereas the _LINC00152_ knockdown suppressed migration

and invasion in LoVo cells (Fig. 4b). _LINC00152_ SPONGES MIR-139-5P To investigate underlying mechanisms of _LINC00152_ in CRC, we first measured the subcellular localization of

_LINC00152_ in HCT116 cells, and revealed that _LINC00152_ was localized predominantly in the cell cytoplasm (Fig. 5a), suggesting that _LINC00152_ may regulate tumorigenesis at the

post-transcriptional level. LncRNAs could act as molecular sponges to modulate mRNAs expression by competitively binding their common miRNA responsive elements (MREs). Previous studies have

proved that _LINC00152_ could function as a ceRNA in human cancers19,20,21. We hypothesized that _LINC00152_ could promote CRC tumorigenesis and progression by suppressing the functions of

certain miRNAs. Based on the bioinformatics analysis and Xia’s work22, we found that _LINC00152_ harbors a recognition sequence of miR-139-5p (Fig. 5b). In view of the opposite functions of

miR-139-5p and _LINC00152_ in CRC12,13,14,15,16,17,18, we intended to explore the potential relationship between them in CRC. We first constructed reporter vectors containing _LINC00152_

(pLuc-LINC00152-WT) or its mutant with mutations in the seed sequence of miR-139-5p (pLuc-LINC00152-Mut), and then evaluated this underlying correlation of miR-139-5p with _LINC00152_ using

luciferase reporter assays. We observed that miR-139-5p overexpression led to a marked inhibition in the reporter activity of pLuc-LINC00152-WT compared with that of pLuc-LINC00152-Mut (Fig.

 5c), suggesting sequence-specific binding and inhibition of _LINC00152_ by miR-139-5p. To further validate the potential binding of _LINC00152_ to miR-139-5p, an RNA Immunoprecipitation

(RIP) assay using an anti-Ago2 antibody was performed. The data exhibited that both _LINC00152_ and miR-139-5p were obviously enriched in Ago2 complex, demonstrating that LINC00152 is

included in miRNPs, probably through binding with miR-139-5p (Fig. 5d). _LINC00152_ MODULATES NOTCH1 EXPRESSION BY COMPETITIVELY BINDING MIR-139-5P Previous studies have shown that

miR-139-5p inhibit CRC tumorigenesis, development, and chemoresistance by regulating NOTCH112,13,14,15. To ascertain whether the above-observed effects depend on the regulation of

_LINC00152_ on the miR-139-5p/NOTCH1 pathway, we first evaluated the relationship among _LINC00152_, miR-139-5p and NOTCH1 using luciferase assays. As a result, the overexpression of

_LINC00152_, but not the vector control, blocked the inhibitory effect of miR-139-5p on the relative luciferase expression of pLuc-NOTCH1-3′UTR (Fig. 5e). These results confirmed that

_LINC00152_ abolishes the miR-139-5p-mediated repressive activity on NOTCH1 by competitively binding miR-139-5p. In addition, _LINC00152_ knockdown significantly reduced the endogenous

NOTCH1 expression in CRC cells (Fig. 5f). In contrast, NOTCH1 expression was obviously increased in _LINC00152_ overexpressing CRC cells (Fig. 5f). A positive relationship was also observed

between the levels of NOTCH1 and _LINC00152_ in CRC tissues (Fig. 5g). These data demonstrate that _LINC00152_ can regulate NOTCH1 activity by sponging miR-139-5p both in CRC cell lines and

clinical CRC tumors. _LINC00152_ EXERTS TUMOR-PROMOTING FUNCTION IN CRC BY REGULATING THE MIR-139-5P/NOTCH1 AXIS Both miR-139-5p and NOTCH1 could regulate cell growth, apoptosis, and

invasion in CRC12,13,14,15,16,17,18, 22. To investigate whether _LINC00152_ exerts tumor-promoting functions in CRC by modulating the miR-139-5p/NOTCH1 axis, we first checked the effects of

miR-139-5p and NOTCH1 on _LINC00152_-induced cell proliferation, and observed that miR-139-5p overexpression or _NOTCH1_ knockdown blocked the _LINC00152_-induced CRC cell growth (Fig. 6a).

We then evaluated the effects of miR-139-5p/NOTCH1 signaling on the _LINC00152_-induced 5-FU resistance in CRC cells. As shown in Fig. 6b, ectopic miR-139-5p expression or _NOTCH1_ knockdown

significantly reversed the _LINC00152_-induced 5-FU resistance and counteracted the apoptosis-inhibiting effects of _LINC00152_ in CRC cells (Fig. 6c). In addition, the increased cell

mobility in _LINC00152_ overexpressing CRC cells was also reversed by miR-139-5p overexpression or _NOTCH1_ knockdown (Fig. 6d). Altogether, these data demonstrate that _LINC00152_ exerts

tumor-promoting functions in CRC, at least partly, through sponging miR-139-5p and then regulating NOTCH1. DISCUSSION In this study, we observed that _LINC00152_ expression is obviously

increased in clinical CRC tissues, and is correlated with tumor stage and poor patient survival. Functionally, we revealed that _LINC00152_ promotes CRC growth, metastasis, and induces 5-FU

resistance. Moreover, we further demonstrated that _LINC00152_ executes tumor-promoting functions by sponging miR-139-5p and then modulating NOTCH1 in CRC. Numerous studies have revealed

varied regulatory roles of lncRNAs in human diseases, especially in tumorigenesis and development23. For example, our previous work revealed that _UCA1_ could promote cell proliferation and

5-FU chemoresistance in CRC via competitively inhibiting miR-204-5p24. _LINC00152_ is recently identified cancer-related lncRNA that play oncogenic roles in several kinds of human cancers,

especially in digestive tract tumors4,5,6,7,8,9, 11. Yue et al.19 reported that _LINC00152_ expression is increased in CRC. Interestingly, in contradictory to their conclusions, a recently

published work demonstrated that _LINC00152_ is downregulated in CRC, inhibits viability and promotes apoptosis of CRC cells25. Here, we demonstrated that _LINC00152_ expression was

obviously increased in CRC and correlated with patient’s survival, which was also observed by Yue et al.19. Our detailed functional studies revealed the promoting effects of _LINC00152_ on

CRC growth and metastasis, which is coincident with the oncogenic role of _LINC00152_ in GC4,5,6,7, liver cancer8, gallbladder cancer9, 26, and clear cell renal cell carcinoma27. In

addition, we also showed that _LINC00152_ confers resistance to 5-FU-induced apoptosis, which was similar to that reported by Yue et al.19. In their study, Yue et al. demonstrated that

_LINC00152_ works as a ceRNA of miR-193a-3p to induce oxaliplatin resistance. These data demonstrate that _LINC00152_ is a key lncRNA with extensive tumor-promoting functions in human

cancers. Several studies have reported that _LINC00152_ promotes tumor development and progression by regulating several key tumor-related pathways, including EGFR, mTOR, and PI3K/AKT

signaling4, 8, 9. Recent studies revealed a new mechanism of lncRNA by acting as ceRNA20. In this situation, lncRNAs can block the repression of miRNA on its target genes by competitively

binding their common MREs28. _LINC00152_ could bind several miRNAs in cancer cells, including miR-138, miR-376c-3p, and miR-193a-3p19, 25, 26, suggesting that ceRNA is a key mechanism by

which _LINC00152_ regulates tumorigenesis and development. Due to the upregulation and tumor-promoting role of _LINC00152_ in CRC, it is reasonably concluded that _LINC00152_ promotes CRC

development and progression by inhibiting tumor suppressive miRNAs. Based on previous works by us and other researchers, miR-139-5p levels are markedly reduced in CRC, and has exact opposite

functions to those of _LINC00152_12,13,14,15,16,17,18. MiR-139-5p can repress CRC growth, metastasis, and chemoresistance by regulating several genes, such as NOTCH1, BCL2, and

AMFR12,13,14,15,16,17,18. MiR-139-5p was reported to play a suppressive role in other cancers, including gastric, breast, and hepatocellular carcinoma29. As a key member of the NOTCH family,

NOTCH1 is frequently upregulated in human cancers, including CRC30. Previous researches have proved that miR-139-5p can regulate CRC growth, metastasis, stemness, and chemoresistance via

targeting NOTCH112,13,14,15, 31. We speculated that _LINC00152_ exerts its functions by regulating the miR-139-5p/NOTCH1 pathway. As expected, both the luciferase and RIP assays confirmed

the binding of _LINC00152_ to miR-139-5p. Subsequent functional and mechanistic assays proved that _LINC00152_ regulates CRC development, progression, and drug resistance by competitively

sponging miR-139-5p and then restoring NOTCH1 activity. In summary, our work shows that _LINC00152_ is upregulated in CRC, correlated with patients’ survival and appears to be a potential

biomarker for predicting chemoresistance. _LINC00152_ contributes to the tumorigenesis, progression, and chemoresistance of CRC by inhibiting miR-139-5p, uncovering a novel ceRNA network of

_LINC00152_/miR-139-5p/NOTCH1 in CRC cells. These data suggest that targeting _LINC00152_ may be a promising therapeutic strategy for CRC. MATERIALS AND METHODS CLINICAL SAMPLES A total of

108 paired human CRC tissues and NCTs were collected with informed consent at Affiliated Hospital of Jiangnan University, and the detailed patient information are shown in Table 1. This

study was carried out under the permission of the Clinical Research Ethics Committees of Affiliated Hospital of Jiangnan University. CELL LINES HEK-293T and six CRC cell lines (HCT8, HT29,

LoVo, HCT116, SW480, and SW620) were obtained from the American Type Culture Collection. These cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10%

fetal bovine serum (Gibco, USA) and have been recently authenticated. RNA ISOLATION AND QUANTITATIVE REVERSE TRANSCRIPTION (RT)-PCR ASSAYS Total RNA was isolated with RNAiso Plus (Takara,

Japan). Cytoplasmic and nuclear RNA was purified using PARISTM Kit (Ambion, USA). Complimentary DNA was synthesized using the HiFiScript 1st Strand cDNA Synthesis Kit (CWBIO, China). Real

time RT-PCR was performed using an UltraSYBR Mixture (CWBIO). VECTOR CONSTRUCTION AND SIRNA _LINC00152_ was synthesized at GENEray Biotechnology (China) and was inserted into the lentivirus

vector pWPXL. The fragment of _LINC00152_ with miR-139-5p-binding site and the _NOTCH1_ 3'UTR were cloned into pLuc. The _LINC00152_ with the mutated seed sequence of miR-139-5p was

constructed by an overlap extension PCR32. The primers used in vector construction are shown in Supplementary Table 1. The siRNAs of _LINC00152_ and _NOTCH1_ were purchased from GenePharma

(China). GENERATION OF CELL LINES WITH STABLE OVEREXPRESSION OF _LINC00152_ HEK-293T cells were transfected with pWPXL-LINC00152 (or pWPXL), pMD2G, and ps-PAX2 plasmids using Lipofectamine

2000 (Invitrogen, USA). These virus particles were centrifuged and filtered to infect HCT116 and HT29 cells to generate corresponding stable cells. CELL PROLIFERATION AND COLONY FORMATION

ASSAYS Cell Counting Kit 8 (CCK-8, Beyotime, China) was used to measure cell viability. A colony formation assay was performed as we previously described33. CELL CYCLE AND APOPTOSIS ANALYSES

The cell cycle and apoptosis analyses of _LINC00152_-overexpressed and silenced CRC cells were applied using the Cell Cycle and Apoptosis Detection Kit purchased from CWBIO. CELL MIGRATION

AND INVASION ASSAY Transwell assays were performed to measure cell migration and invasion using Boyden chambers (8-mm pore size, BD Biosciences) as we previously described33. XENOGRAFT TUMOR

ASSAY Twenty-four male athymic nude BALB/c mice at 5 weeks of age were randomly divided into four groups, and the number of mice is determined according to prior experience of our

laboratory. HCT116 cells stably expressing _LINC00152_ or the bank vector were subcutaneously injected into flank of nude mouse. Four (HCT116) or six weeks (HT29) after injection, these mice

were sacrificed to measure the growth of subcutaneous tumors. The investigator was blinded to group allocation during the experiments. All animal experiments were approved by the Clinical

Research Ethics Committees of our Hospital. LUCIFERASE REPORTER ASSAY HEK-293T cells were co-transfected with pLuc, pRL-CMV, miR-139-5p mimics (negative control, NC), and pWPXL-LINC00152

(pWPXL). These cells were then assayed for luciferase activity using the Dual-Luciferase® Reporter Assay System (Beyotime, China). RNA IMMUNOPRECIPITATION (RIP) ASSAY A RIP assay was

performed using the EZ-Magna RIP Kit (Millipore, USA) as we previously described24. WESTERN BLOTTING Total protein was separated by 8% (or 10%) sodium dodecyl sulfate polyacrylamide gel

electrophoresis and transferred to a PVDF membrane. After blocking with non-fat milk, the polyvinylidene difluoride membrane was incubated with a rabbit anti-human NOTCH1 antibody (1:1000,

20687-1-AP, Proteintech, USA) or a mouse anti-β-actin antibody (1:1000, AA128, Beyotime, China). STATISTICAL ANALYSES Data were presented as the mean ± s.d. Student’s _t_-test, the

Mann–Whitney _U_-test and the _χ_2 test were performed to analyze the differences among different groups. The differences in survival rates were determined by the Kaplan–Meier method and

compared by the log-rank test. HRs and 95% CIs were calculated by a Cox proportional hazards model. _P_-values < 0.05 were considered statistically significant. CHANGE HISTORY * _ 16

AUGUST 2018 This article was originally published under Nature Research's License to Publish, but now has been made available under a CC BY 4.0 license. The PDF and HTML versions of the

Article have been modified accordingly. _ REFERENCES * Torre, L. A. et al. Global cancer statistics, 2012. _CA Cancer J. Clin._ 65, 87–108 (2015). Article  PubMed  Google Scholar  *

Migliore, L., Migheli, F., Spisni, R. & Coppede, F. Genetics, cytogenetics, and epigenetics of colorectal cancer. _J. Biomed. Biotechnol._ 2011, 792362 (2011). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Xie, X. et al. Long non-coding RNAs in colorectal cancer. _Oncotarget_ 7, 5226–5239 (2016). PubMed  Google Scholar  * Zhou, J. et al. Linc00152 promotes

proliferation in gastric cancer through the EGFR-dependent pathway. _J. Exp. Clin. Cancer Res._ 34, 135 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen W. M. et al. Long

intergenic non-coding RNA 00152 promotes tumor cell cycle progression by binding to EZH2 and repressing p15 and p21 in gastric cancer. _Oncotarget_ 7, 9773–9787 (2016). PubMed  PubMed

Central  Google Scholar  * Pang, Q. et al. Increased expression of long intergenic non-coding RNA LINC00152 in gastric cancer and its clinical significance. _Tumour Biol._ 35, 5441–5447

(2014). Article  CAS  PubMed  Google Scholar  * Li, Q. et al. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. _Tumour Biol._ 36, 2007–2012

(2015). Article  CAS  PubMed  Google Scholar  * Ji, J. et al. LINC00152 promotes proliferation in hepatocellular carcinoma by targeting EpCAM via the mTOR signaling pathway. _Oncotarget_ 6,

42813–42824 (2015). PubMed  PubMed Central  Google Scholar  * Cai, Q. et al. Upregulation of long non-coding RNA LINC00152 by SP1 contributes to gallbladder cancer cell growth and tumor

metastasis via PI3K/AKT pathway. _Am. J. Transl. Res._ 8, 4068–4081 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Chen, Q. N. et al. Long intergenic non-coding RNA 00152 promotes

lung adenocarcinoma proliferation via interacting with EZH2 and repressing IL24 expression. _Mol. Cancer_ 16, 17 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tani, H.

& Torimura, M. Identification of short-lived long non-coding RNAs as surrogate indicators for chemical stress response. _Biochem. Biophys. Res. Commun._ 439, 547–551 (2013). Article  CAS

  PubMed  Google Scholar  * Song, M. et al. MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1. _Protein Cell_ 5, 851–861 (2014). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Zhang, L. et al. microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer. _Mol. Cancer_ 13, 124 (2014). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Liu, H. et al. miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1. _Pathol. Res. Pract._ 212, 643–649

(2016). Article  CAS  PubMed  Google Scholar  * Xu, K. et al. MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.

_Oncotarget_ 7, 75118–75129 (2016). PubMed  PubMed Central  Google Scholar  * Li, Q. et al. miR-139-5p inhibits the epithelial-mesenchymal transition and enhances the chemotherapeutic

sensitivity of colorectal cancer cells by downregulating BCL2. _Sci. Rep._ 6, 27157 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shen, K. et al. MiR-139 inhibits invasion

and metastasis of colorectal cancer by targeting the type I insulin-like growth factor receptor. _Biochem. Pharmacol._ 84, 320–330 (2012). Article  CAS  PubMed  Google Scholar  * Zou, F. et

al. Targeted deletion of miR-139-5p activates MAPK, NF-kappaB and STAT3 signaling and promotes intestinal inflammation and colorectal cancer. _FEBS J._ 283, 1438–1452 (2016). Article  CAS 

PubMed  Google Scholar  * Yue, B., Cai, D., Liu, C., Fang, C. & Yan, D. Linc00152 functions as a competing endogenous rna to confer oxaliplatin resistance and holds prognostic values in

colon cancer. _Mol. Ther._ 24, 2064–2077 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yang, C. et al. Competing endogenous RNA networks in human cancer: hypothesis,

validation, and perspectives. _Oncotarget_ 7, 13479–13490 (2016). PubMed  PubMed Central  Google Scholar  * Xia, T. et al. Long noncoding RNA associated-competing endogenous RNAs in gastric

cancer. _Sci. Rep._ 4, 6088 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fender, A. W., Nutter, J. M., Fitzgerald, T. L., Bertrand, F. E. & Sigounas, G. Notch-1

promotes stemness and epithelial to mesenchymal transition in colorectal cancer. _J. Cell Biochem._ 116, 2517–2527 (2015). Article  CAS  PubMed  Google Scholar  * Wang, K. C. & Chang, H.

Y. Molecular mechanisms of long noncoding RNAs. _Mol. Cell_ 43, 904–914 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bian, Z. et al. LncRNA-UCA1 enhances cell

proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p. _Sci. Rep._ 6, 23892 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang, Y. H.,

Fu, J., Zhang, Z. J., Ge, C. C. & Yi, Y. LncRNA-LINC00152 down-regulated by miR-376c-3p restricts viability and promotes apoptosis of colorectal cancer cells. _Am. J. Transl. Res._ 8,

5286–5297 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Cai, Q. et al. Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by

regulating HIF-1alpha via miR-138. _Open Biol_. 7, 160247 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wu, Y. et al. Long non-coding RNA Linc00152 is a positive prognostic

factor for and demonstrates malignant biological behavior in clear cell renal cell carcinoma. _Am. J. Cancer Res_. 6, 285–299 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Rashid,

F., Shah, A. & Shan, G. Long non-coding rnas in the cytoplasm. _Genomics Proteomics Bioinformatics_ 14, 73–80 (2016). Article  PubMed  PubMed Central  Google Scholar  * Zhang, H. D.,

Jiang, L. H., Sun, D. W., Li, J. & Tang, J. H. MiR-139-5p: promising biomarker for cancer. _Tumour Biol._ 36, 1355–1365 (2015). Article  CAS  PubMed  Google Scholar  * Chu, D. et al.

High level of Notch1 protein is associated with poor overall survival in colorectal cancer. _Ann. Surg. Oncol._ 17, 1337–1342 (2010). Article  PubMed  Google Scholar  * Vinson, K. E.,

George, D. C., Fender, A. W., Bertrand, F. E. & Sigounas, G. The Notch pathway in colorectal cancer. _Int. J. Cancer_ 138, 1835–1842 (2016). Article  CAS  PubMed  Google Scholar  *

Huang, Z. et al. MicroRNA-95 promotes cell proliferation and targets sorting Nexin 1 in human colorectal carcinoma. _Cancer Res._ 71, 2582–2589 (2011). Article  CAS  PubMed  Google Scholar 

* Yin, Y. et al. miR-204-5p inhibits proliferation and invasion and enhances chemotherapeutic sensitivity of colorectal cancer cells by downregulating RAB22A. _Clin. Cancer Res._ 20,

6187–6199 (2014). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The study was supported by grants from National Natural Science Foundation of China (81672328,

81602033, 81272299, and 81301784), Natural Science Foundation of Jiangsu Province (BK20150004 and BK20151108), Medical Key Professionals Program of Jiangsu Province, Fundamental Research

Funds for the Central Universities (JUSRP51710A and NOJUSRP51619B), Medical Innovation Team Program of Wuxi, and Hospital Management Center of Wuxi (YGZXZ1401 and YGZXM1524). AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China Zehua Bian, Jiwei Zhang, Min Li, Yuyang Feng, Surui

Yao, Mingxun Song, Yuan Yin, Dong Hua & Zhaohui Huang * Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China Xiaowei Qi * Department of

Surgical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China Bojian Fei * Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi,

Jiangsu, 214062, China Dong Hua Authors * Zehua Bian View author publications You can also search for this author inPubMed Google Scholar * Jiwei Zhang View author publications You can also

search for this author inPubMed Google Scholar * Min Li View author publications You can also search for this author inPubMed Google Scholar * Yuyang Feng View author publications You can

also search for this author inPubMed Google Scholar * Surui Yao View author publications You can also search for this author inPubMed Google Scholar * Mingxun Song View author publications

You can also search for this author inPubMed Google Scholar * Xiaowei Qi View author publications You can also search for this author inPubMed Google Scholar * Bojian Fei View author

publications You can also search for this author inPubMed Google Scholar * Yuan Yin View author publications You can also search for this author inPubMed Google Scholar * Dong Hua View

author publications You can also search for this author inPubMed Google Scholar * Zhaohui Huang View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to Zhaohui Huang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. ADDITIONAL INFORMATION PUBLISHER'S

NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ELECTRONIC SUPPLEMENTARY MATERIAL SUPPLEMENTARY TABLE S1. PRIMER

SEQUENCES RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and

reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if

changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the

material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to

obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Bian, Z., Zhang, J., Li, M. _et al._ Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting

miR-139-5p. _Oncogenesis_ 6, 395 (2017). https://doi.org/10.1038/s41389-017-0008-4 Download citation * Received: 22 May 2017 * Revised: 18 August 2017 * Accepted: 21 September 2017 *

Published: 28 November 2017 * DOI: https://doi.org/10.1038/s41389-017-0008-4 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative